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ReviewSeptember 15, 2016

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry
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Cite this: Chem. Rev. 2016, 116, 19, 12150–12233

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https://doi.org/10.1021/acs.chemrev.6b00274

Published September 15, 2016

Abstract

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The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last five years up to the end of 2015. These methods are clustered by strategies for preparation of the ring and further derivatization of preformed oxetane-containing building blocks. Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally, examples of oxetane derivatives in ring-opening and ring-expansion reactions are described.

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1 Introduction

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Oxetanes, as strained cyclic ethers, present a fascinating combination of stable motifs for medicinal chemistry and reactive intermediates for further synthesis. These features make them attractive motifs for an ever-increasing range of applications in the chemical sciences. In medicinal chemistry, oxetanes have received enormous interest as replacement groups for gem-dimethyl and carbonyl groups with improved physicochemical properties. The small, polar nature of the heterocycle has led to its incorporation as a pendant motif to improve “druglike” properties, in particular solubility, and also to offer intellectual property advantages. As a result, these units have been widely adopted in medicinal chemistry programs in recent years. These recent studies have relied on both established synthetic methods and development of numerous new methodologies for oxetane synthesis and incorporation. Accordingly, a number of novel methods have been developed to access oxetane-containing compounds. At the same time, there have been significant advances in utilizing the reactivity of oxetanes in the synthesis of complex molecules. The strain in the small ring facilitates opening with nucleophiles, rearrangements, and ring expansions. Here, we review and collate the synthetic methods and reactivity of oxetanes, as well as commenting on the relevance to medicinal chemistry programs. Advances up to late 2015 are included, concentrating on more recent developments but also detailing older work that still remains powerful in the synthesis of varied oxetane derivatives.

Section 2 will introduce structural features of the oxetane ring and properties that the ring can impart in a medicinal chemistry context. The following sections then examine oxetane synthesis through ring-closing approaches, with the cyclization step forming a C–O or C–C bond (section 3), and (formal) [2+2] cycloadditions forming both C–C and C–O bonds (section 4). Selected transformations of oxetane-containing products are discussed in each section to illustrate the stability of the ring to chemical transformations, as are selected applications of biologically active products. Section 5 examines strategies available for the incorporation of intact oxetane motifs, including the use of Carreira’s oxetan-3-one and other small oxetane-containing building blocks that maintain the small ring. This section also includes a survey of the use of these building blocks in medicinal chemistry applications, with selections covering primary literature and also patent literature. Section 6 continues the functionalization of intact oxetane derivatives through metalation. Section 7 focuses specifically on 2-exo-methyleneoxetanes and their synthesis and functionalization, in both ring-opening reactions and methods that maintain the ring structure leading to functionalized oxetane derivatives. Section 8 reviews ring-opening and ring-expansion reactions of oxetanes, where the four-membered ring is modified to generate new structural types. Readers are also directed to other notable and complementary reviews incorporating varied aspects of oxetane chemistry from Carreira and co-workers, (1, 2) Abe, (3) D’Auria and Racioppi, (4) De Kimpe and co-workers, (5) Mahal, (6) Malapit and Howell, (7) Sun and co-workers, (8) and others. (9-11) The extensive use of oxetane motifs in other fields, including polymer chemistry as a monomer (12-18) and a cross-linker (19, 20) and, for example, in catalytic reaction with CO₂ to generate cyclic carbonates, (21-27), is outside the scope of this review and will not be considered. (28-30)

2 Properties and Natural Occurrence of Oxetanes and Their Influence on Biologically Relevant Physicochemical Properties

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2.1 Physical Properties of Oxetanes

Oxetane itself is a four-membered ring containing an oxygen atom with an inherent ring strain of 106 kJ·mol^–1 [epoxides 112 kJ·mol^–1; tetrahydrofurans (THFs) 25 kJ·mol^–1]. (31, 32) The ring adopts an essentially planar structure with a puckering angle of only 8.7° at 140 K (10.7° at 90 K) as indicated in an X-ray crystal structure of the parent heterocycle (Figure 1a). (33, 34) The planar structure minimizes the strain in the ring, and due to the presence of the heteroatom, there are considerably fewer gauche interactions, which are reduced by puckering, than in cyclobutane (cf. 30° puckering for cyclobutane). (35)

Figure 1. Structural properties of oxetane and puckering of the substituted oxetane ring in EDO.

The introduction of substituents onto the oxetane ring can increase the unfavorable eclipsing interactions, resulting in a more puckered conformation. For example, X-ray crystallographic investigations showed that the puckering angle of the biodegradable insecticide EDO was 16° (Figure 1b). (36) The carbon–oxygen bond length in unsubstituted oxetane is 1.46 Å and the carbon–carbon bond length is 1.53 Å, which results in bond angles of 90.2° (C–O–C), 92.0° (C–C–O), and 84.8° (C–C–C), by X-ray at 90 K. (34) The strained C–O–C bond angle exposes the oxygen lone pair of electrons, allowing the oxetane to act as an excellent hydrogen-bond acceptor as well as Lewis base. (37) As required for hybridization in small rings, there is increased p-character to the bonds in the ring, and exo-cyclic substituents have increased bond angles. The increasing s-character of the oxygen lone pairs as the ring size of the cyclic ether decreases does not have a significant influence on the H-bonding ability until three-membered epoxides. Consequently, oxetanes form more effective H-bonds than other cyclic ethers. (38, 39) Similarly, oxetanes compete as H-bond acceptors with the majority of carbonyl functional groups (aliphatic ketones, aldehydes, and esters), (40, 41) with only amides providing better acceptors. (42, 43) These structural features are important for many of the advantageous properties of substituted oxetanes.

2.2 Oxetanes in Natural Products

The oxetane ring appears in relatively few natural product structures, but when it is present, there is important biological activity that is often reliant on the ring (Figure 2). Perhaps the most well-known example is paclitaxel, or Taxol, first isolated in 1971 from the stem bark of the western yew (Taxus brevifolia) and used in cancer chemotherapy. (44) Taxol acts by binding to microtubules and stabilizing them during cell division. (45) Computational studies concluded that the oxetane acted as a conformational lock, rigidifying the structure, (46) or alternatively as a hydrogen-bond acceptor. (45) Although lower activity was observed when the oxetane was replaced with related alternative ring structures, (45, 47, 48) very recent studies have shown that the oxetane is not in fact essential for biological activity. (49) In the purported biosynthesis of taxol, cyclization occurs via an enzyme-mediated epoxy ester/oxetane ester rearrangement mechanism. Three separate mechanisms for this transformation have been proposed: a neutral-concerted pathway (Figure 3a), (50) an acid-catalyzed route (Figure 3b), (51) and a dissociative pathway (Figure 3c). (52) Computation studies by Willenbring and Tantillo (53) were unable to find evidence to conclusively distinguish among the three mechanisms.

Figure 2. Oxetane-containing natural products.

Figure 3. Three proposed pathways for biosynthesis of the oxetane ring of taxol.

Various other oxetane-containing compounds have been isolated from natural sources. Oxetanocin A was first isolated from the soil bacteria Bacillus megaterium and inhibits the in vivo replication of human immunodeficiency virus (HIV). (54) Oxetin was isolated from a broth of Streptomyces sp. OM-2317 and has antibacterial and herbicidal effects. (55) It was reported to inhibit Bacillus subtilis and Piricularia oryzae in minimal media, as well as showing herbicidal activity, inhibiting glutamine synthetase from spinach leaves. Both maoyecrystal I and mitrephorone A were shown to be cytotoxic. (56, 57) Thromboxane A₂ has prothrombotic properties, and the oxetane is very short-lived in the body due to the acetal structure. (58) Merrilactone A was first isolated in 2000 from the pericarps of the Illicium merrillianum plant and was shown to stimulate the growth of rat neurons. (59) Dictyoxetane is a marine diterpene isolated from the brown alga Dictyota dichotome whose biological properties are currently not understood. (60) This pentacyclic structure has been subject to a synthetic model study targeting the unusual tricyclic heterocyclic portion. (61) Finally, bradyoxetin, produced by the soil bacterium Bradyrhizobium japonicum, has two pendant oxetane rings. (62)

2.3 Oxetanes as Replacement Groups

In 2006, Carreira, Rogers-Evans and co-workers (63-65) (Hofmann-La Roche) published a highly influential report on the use of 3,3-disubstituted oxetanes as replacement groups for gem-dimethyl groups in medicinal chemistry (Figure 4). gem-Dimethyl groups have commonly been used in medicinal chemistry to block metabolically vulnerable methylene sites. However, their introduction results in an increase in lipophilicity, which itself may have adverse effects on the pharmacokinetic properties of a compound. (66) This work exploited the similar molecular volume of the oxetane and gem-dimethyl groups (67, 68) to propose the oxetane motif as a considerably more polar equivalent of a gem-dimethyl group with the same spacial arrangement. The replacement afforded a reduction in lipophilicity (cLogP), which can give an associated reduction in metabolic liability.

Figure 4. 3,3-Disubstituted oxetanes as replacement group for *gem*-dimethyl.

To probe the effect of the replacement of a gem-dimethyl unit with an oxetane, the t-butyl group of a model compound, 1, was replaced with a methyl-substituted oxetane, 2 (Figure 5). (63) The parent compound chosen was both lipophilic and amphiphilic, but it became considerably more polar and more soluble upon introduction of oxetane. In addition, the metabolic stability was improved as indicated by reduced intrinsic clearance rates (CL_int; microliters per minute per milligram) measured in human (h) and mouse (m) liver microsomes. Oxetane-containing compound 2 was also shown to be have reduced hERG (human ether-a-go-go-related gene) inhibition (hERG IC₅₀ 35 μM for 2 vs 7.5 μM for 1) due to the reduction in lipophilicity. (63, 65)

Figure 5. Effects of replacing a *gem-*dimethyl group with oxetane.

The strong σ-electron-withdrawing properties of the oxetane ring were shown to attenuate the basicity of nearby amines. Through an “oxetane scan”, the greatest effects were seen when the oxetane was in α-position to the amine, but interestingly, a decrease of 0.3 pK_a unit was still observed when the oxetane was in δ-position to the amine compared to the parent compound (Figure 6). The chemical stability of these compounds, including 2–6, was shown to be high in aqueous buffers over the pH range 1–10 for 2 h at 37 °C. (63)

Figure 6. Effect of oxetane motif on amine basicity.

In a subsequent series of papers, Carreira and co-workers (1, 2, 65, 69) investigated various properties of oxetanes as replacement groups, resulting in a number of advantageous changes. In particular, the use of oxetanes as replacements for carbonyl groups has been of considerable interest due to similar dipoles and H-bonding properties (Figure 7). (69) Whereas carbonyl compounds (aldehydes, ketones, and esters) are vulnerable to enzymatic attack and α-deprotonation/epimerization of stereogenic centers, oxetane derivatives are stable to both of these concerns. As a replacement, the main difference between an oxetane and carbonyl motif is the length of the group. Fujishima et al. (70, 71) employed this strategy and the increased size of the oxetane to improve the binding affinity of 1,25-dihydroxyvitamin D₃ analogues for bovine thymus vitamin D receptor.

Figure 7. Comparison between carbonyl and oxetane functional groups, representing similar arrangement of lone pairs and change in size.

Carreira and co-workers (69) studied the physiochemical and biological properties of various matched pairs of oxetane-containing spirocyclic compounds and their corresponding carbonyl-containing heterocycle derivatives (Table 1). In both the pyrrolidine and piperidine derivative pairs, 7/8 and 9/10, incorporation of the oxetane ring decreased solubility. However, opposing effects on lipophilicity were observed. On the other hand, metabolic stability was considerably improved for oxetane spirocycles 8 and 10 compared to 7 and 9 in terms of the intrinsic clearance rate.

Table 1. Physicochemical and Biological Properties Demonstrating the Effects of Replacing a Carbonyl Group with an Oxetane Ring^a

^{Table a}

Intrinsic clearance rates were measured in human (h) and mouse (m) liver microsomes.

Morpholine rings are often incorporated into drug scaffolds to improve aqueous solubility, but they can also undergo undesirable oxidative metabolism. Due to similar structural properties, the spirocyclic oxetane motif 12 was suggested as a morpholine replacement. When compared to morpholine 11, spirocyclic oxetane 12 had increased aqueous solubility and decreased lipophilicity while remaining metabolically stable toward oxidation (Table 1). In recent years, Carreira and co-workers have also reported spirocyclic structures as structural analogues of heterocycles, including piperazine (72) as well as piperidine and thiomorpholine analogues, (73) and other spirocyclic small-ring heterocyclic systems targeting drug discovery. (74-78)

In 2008, Duncton et al. (79) examined the stability of a series of oxetane derivatives on incubation with human liver microsomes in the presence of glutathione and nicotinaide adenine dinucleotide phosphate (NADPH), to screen for reactive metabolites (Figure 8). Glutathione conjugates were observed for fewer than half the derivatives tested, which was interpreted as providing evidence that the oxetan-3-yl chemotype could be attractive for medicinal chemistry.

Figure 8. Examples of oxetanes tested with human liver microsomes and glutathione.

In 2013, Carreira and co-workers (80) explored the effects of structural modification of thalidomide and lenalidomide. Infamously, while the R-isomer of thalidomide functions as an anti-emetic and sedative, the S-isomer is a teratogen. Crucially, these readily interconvert under physiological conditions. When the imide C═O was replaced by an oxetane, an increase in solubility and decrease in lipophilicity, and no unfavorable difference in the intrinsic clearance rates in human microsomes, was observed (Table 2). (80) Oxetanothalidomide 13 was shown to be configurationally stable to racemization in human blood plasma after an incubation period of 5 h, thereby showing that oxetanes as replacements of carbonyl groups can alleviate epimerization at adjacent stereocenters.

Table 2. Comparison of Physicochemical Properties of Thalidomide and Oxetanothalidomide

Dowling et al. (81) at AstraZeneca compared 3-aminooxetane motifs with other small rings through a series of matched pairs (Figure 9). It was found that introduction of oxetane lowered logD by ∼0.8 unit in comparison to aminocyclopropane and aminocyclobutane derivatives. In addition, the oxetane derivative significantly decreased the fraction of compound bound by human plasma proteins, increased metabolic stability (rat liver microsome and hepatocyte), and reduced hERG ion channel binding.

Figure 9. Matched-pair analysis of logD for 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase.

While 3-substituted oxetanes have now been relatively well explored in this manner and have been exploited accordingly (see section 5), there remain fewer examples and little data on other oxetane substitution patterns being examined in any detail in this context. The most notable study that compared oxetane substitution patterns, from Stepan et al. (82) (Pfizer), studied the effect of different carbocyclic and oxygen heterocylic derivatives on a series of N-substituted arylsulfonamides. Progression from carbocyclic rings to six- and five-membered oxygen heterocycles and eventually oxetane rings gave an improvement in metabolic stability without reduction in potency (Figure 10). Across THF derivatives, the 3-substituted example was more stable to human liver microsomes (HLM) than the 2-substituted derivative; similarly, the 3-monosubstituted oxetane was more stable than the 2-monosubstituted derivative. Metabolite identification studies, which initially identified N-alkyl substituents as metabolically labile, were able to identify sites of oxidative metabolism. For the 2-monosubstituted oxetane derivative, the compound underwent ring scission, forming hydroxy acid and diol metabolites. For the 3-monosubstituted oxetane derivative, the major metabolic route was oxidation of the bridging methylene carbon leading to N-dealkylation. Incorporation of gem-dimethyl substitution at the oxetane 4-position gave the most stable derivative (CL_int 25.9 mL·min^–1·kg^–1), whereas a gem-dimethyl group at the 3-position afforded a considerably less stable example (CL_int > 293 mL·min^–1·kg^–1). This study concluded that introduction of an oxetane could increase the overall drug likeness of molecules. Further studies examining oxidative metabolism showed this was largely due to CYP3A4 and that metabolic stability was directly linked to intrinsic lipophilicity. (83, 84) As such, oxetane derivatives benefited from their increased polarity compared to other cyclic ethers.

Figure 10. Comparison of metabolic stability of N-substituted arylsulfonamides. CL_int,app is total intrinsic clearance obtained from scaling in vitro HLM half-lives.

Bull and co-workers (85) have reported studies into the chemical and metabolic stability of 2-sulfonyloxetanes, which were designed as novel fragments for fragment-based drug discovery. Selected compounds were shown to be stable across the pH range 1–10, with half-lives in the region of 4–5 days at 25 °C. Similarly, the intrinsic clearance of 2-(2-pyridylsulfonyl)oxetane was investigated in rat hepatocytes and shown not to present a metabolic liability. Oxetane δ-amino acid scaffolds, synthesized by Wessel and co-workers (86-88) at Roche, were used to generate an oxetane-based library of oxadiazoles and triazoles. (89) Typical physicochemical properties were calculated for the oxetane library, and found to be within desirable ranges for medicinal chemistry (Figure 11). Metabolic properties, in particular the oxetane derivatives’ susceptibility toward degradation in human and mouse microsomes, were evaluated for a selection of substrates. All oxadiazoles tested displayed medium to low clearance in either human or mouse microsomes.

Figure 11. Examples from Wessel’s oxetane library.

Wipf and co-workers (90, 91) recently developed an oxetane-containing neutral solubilizing group by adapting an oxetanyl dimethyl sulfoxide (DMSO) derivative that had proved effective as an additive to enhance aqueous solubility of small organic molecules. The oxetanyl sulfoxide motif was incorporated into poorly soluble drugs or drug candidates, particularly those containing an ionizable group (Figure 12). (90) For example, carboxylic acids were transformed into oxetanyl sulfoxide ester derivatives, and amines, used as the hydrochloride salt to improve solubility, were converted into the corresponding oxetanyl sulfoxide carbamates. For a naproxen derivative, oxetanyl sulfoxide derivative 14 showed a >10-fold increase in solubility and also a significant increase in cell permeability. A similar increse in solubility was achieved by converting free amines to oxetanyl sulfonyl carbamates. A bioactive mitochondrial-targeted nitroxide, JP4-039, currently in development, saw a very large (76-fold) solubility increase when the t-butyl carbamate was converted into oxetanyl sulfoxide derivative 15.

Figure 12. Wipf’s oxetane-containing neutral solubilizing group.

These studies and the presence of oxetanes in biologically active compounds have established the oxetane motif as an intriguing structure in medicinal chemistry. Introduction of an oxetane can beneficially influence solubility, metabolic stability, and lipophilicity of a compound as well as influence the basicity of proximal amines. The small polar core may provide the possibility to increase steric bulk without increasing lipophilicity. (63) As a result of these desirable properties, oxetanes have recently received significant interest from the pharmaceutical industry, often being employed as bioisosteres and to improve the physicochemical properties of druglike compounds (see section 5 particularly). (92-94) Recent trends in medicinal chemistry have sought to incorporate motifs that are more sp³-rich, that reduce planarity and improve solubility and other physicochemical properties, without a significant increase in molecular weight; (95-97) the small, polar oxetane motif may offer opportunities toward these goals (this section and section 5). The defined three-dimensional “scaffolding” properties of oxetanes have been exploited as sugar mimics (sections 3.1.4 and 7), and oxetanes have been investigated as amide replacements in unnatural peptides (section 3.1.2 and section 5.1). The subsequent sections will cover the synthesis of varied oxetane derivatives, with examples of the exploitation of the property changes brought about through oxetane incorporation, and also the reactivity of oxetane derivatives.

3 Synthesis of Oxetane Derivatives by Intramolecular Cyclization

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The inherent ring strain in oxetane products makes cyclization a fundamental synthetic challenge, and the kinetics of cyclization to form four-membered saturated cyclic ethers are significantly slower than for three-, five-, and six-membered analogues. (98) Hence anions and good leaving groups are commonly required to achieve acceptable yields for the cyclization of functionalized acyclic precursors to oxetane derivatives. The most common disconnection forms the C–O bond through an intramolecular etherification reaction, which has been achieved by several approaches (section 3.1), complemented by few but increasing C–C bond-forming methods (section 3.2).

3.1 Cyclization through C–O Bond Formation

3.1.1 Intramolecular Etherification

Williamson etherification describes a general approach to ether synthesis by a base-mediated nucleophilic substitution reaction between an alcohol and an aliphatic carbon center in a 1,3-relationship for oxetane synthesis. Intramolecular cyclization generally provides the desired oxetane products; however, the yields can be modest due to undesirable side reactions, such as Grob fragmentation of the halo-alkoxide into an aldehyde and an alkene. (99, 100) Consequently, intramolecular Williamson etherification as a method for oxetane synthesis is rather substrate-dependent. This approach was first used for the synthesis of oxetane in 1878 by Reboul (101) and remains most commonly employed in the synthesis of complex oxetane-containing structures. (102-105)

Nelson and co-workers (106, 107) reported a stereocontrolled synthesis of 2,4-substituted oxetanes from 1,3-diols (Scheme 1). The syn- and anti-diols 16 and 20 were synthesized from the same aldol precursor by stereoselective reduction. (108, 109) Selective synthesis of acetoxybromides 17 and 21 from the 1,3-diols was achieved with inversion of stereochemistry by conversion to the ortho esters followed by treatment with acetyl bromide. The required 1-hydroxy-3-bromo relationship present in intermediates 18 and 22 was established by use of diisobutylaluminium hydride (DIBAL) to cleave the acetyl group. Intramolecular cyclization to oxetanes 19 and 23 was then achieved with complete inversion of stereochemistry by use of sodium hydride in THF, resulting in overall retention of stereochemistry (through double inversion at the benzylic center) over three steps from the 1,3-diol. Interestingly, with a methyl in the 3-position of the oxetane product, a mixture of diastereoisomers was observed, which was speculated to be due to formation of a benzylic cation (not shown). A one-pot procedure for conversion of 17 to 19 was also developed, removing the need for DIBAL reduction, by addition of 1 equiv of MeOH and excess base.

Scheme 1. Stereocontrolled Synthesis of Oxetanes 19 and 23 from the Corresponding Diols

An important enantioselective synthesis of oxetanes was reported in 1986 by Soai et al. (110) Three examples of enantioenriched 2-aryl-substituted oxetanes were prepared through enantioselective reduction of β-halo ketones followed by Williamson ether cyclization promoted by KOH. Enantiomeric excesses of 79–89% were achieved by enantioselective reduction with a chiral reducing catalyst, generated in situ from lithium borohydride and chiral ligand 24. Acetylation followed by subsequent ring closure afforded oxetanes without racemization (Scheme 2a).

Scheme 2. Asymmetric Synthesis of 2-Aryloxetanes by Use of a Chiral Catalyst

More recently, Lo and Fu (111) demonstrated the preparation of enantioenriched oxetanes by the same approach from enantioenriched γ-chlorohydrins. These were, in turn, synthesized from β-chloroketones via an asymmetric reduction with (+)-B-chlorodiisopinocampheylborane [(+)-DIP-Cl; Scheme 2b]. (112) The cyclization used KH, and while the yield was moderate, the enantiomeric excess (ee) was retained. Dussault et al. (113) reported the preparation of enantioenriched oxetanes via cyclodehydration of enantioenriched 1,3-diols, generated from 2,3-epoxy alcohols by ring opening with sodium bis(2-methoxyethoxy)aluminum dihydride (RedAl) or dimethyl cuprate (Scheme 3). The use of KOtBu in THF for both monotosylation and cyclization gave the oxetanes in high yield, either as a one-pot reaction or through isolation of the monotosylate.

Scheme 3. Stereocontrolled Synthesis of Oxetanes from Epoxy Alcohols

In 2006, Mandal and co-workers (114) reported one-pot synthesis of a variety of cyclic ethers, including oxetanes, using a Williamson etherification protocol. Starting from the desired diol, conversion of the primary alcohol to the iodide through an Appel reaction, followed by treatment with base, generated oxetanes 25 and 26 in 82% and 78% yield, respectively (Scheme 4). [See sections 3.1.3 and 3.1.4 for oxetane-containing sugar derivatives and nucleoside analogues.]

Scheme 4. Synthesis of Oxetanes 25 and 26 through an Iodination–Williamson Etherification Pathway

The first synthesis of oxetin employed a traditional Williamson etherification with a tosylate leaving group to give the oxetane ring motif with the desired stereochemistry. Omura and co-workers (115) synthesized the natural product and its three stereoisomers, using a sugar as a chiral auxiliary (Scheme 5a). From aldehyde 27, (116) a Wittig reaction afforded both cis- and trans-alkenes with poor selectivity (1.3:1 cis/trans), but they could be separated by chromatography. Reduction of the ester moiety with DIBAL accessed both allylic alcohols in good yields, and epoxidation of the cis-allylic alcohol with m-chloroperoxybenzoic acid (m-CPBA) gave both possible stereoisomers of epoxide 28a/b. Regio- and stereoselective ring opening of epoxide 28a with NaN₃ afforded a single product with an excellent 81% yield. Selective tosylation of the primary alcohol, followed by Williamson etherification with KOtBu, afforded oxetane 29 in good yield. Functional group manipulation afforded the natural product 30, which was purified by ion-exchange chromatography. The remaining three stereoisomers 31–33 (Scheme 5b) were all prepared by the same synthetic route. Subsequently, all four stereoisomers of oxetin were tested against B. subtilis, but only the natural product oxetin 30 showed any activity.

Scheme 5. (a) Synthesis of the Natural Product Oxetin from d-Glucose and (b) Unnatural Stereoisomers

Synthesis of oxetanocin was achieved by Yamamura and co-workers (117) by use of Williamson etherification for the oxetane-forming step (Scheme 6). A sodium hydride-mediated cyclization was utilized to synthesize the oxetane scaffold of oxetanocin in a good yield of 84% with a mesylate leaving group. Interestingly, the 2-hydroxymethyl substituent could be replaced at C2 with adenine over a sequence of steps involving conversion to the methyl ketone and Baeyer–Villiger oxidation to form the 2-acetate derivative, (118) followed by displacement with protected adenine.

Scheme 6. Synthesis of Oxetanocin by Use of Williamson Etherification for the Key Cyclization Step

Total syntheses of taxol have primarily formed the oxetane ring midway through the sequence by an intramolecular Williamson etherification (Scheme 7). (119-129) The majority of total syntheses use base-mediated approaches for formation of the oxetane on similar intermediates, with the leaving group commonly being either a mesylate, triflate, or halide. Interestingly, mild acidic conditions with catalytic camphorsulfonic acid (CSA) enabled oxetane formation in the sequence of Nicolaou et al., (121) delivering the desired oxetane in just 10 min. The intermediate of Danishefsky et al. (127) differed considerably as the oxetane was introduced in step 13 of 49, considerably earlier than, for example, in the work of Nicolaou et al. (121) (step 31 of 37) or in the total synthesis of Wender et al. (119) (step 40 of 44). Danishefsky stated that this strategy would be important for an analogue program. Treatment with ethylene glycol at reflux allowed the cyclization to occur, and it was speculated by Danishefsky et al. (127) that this transformation involved a hypervalent silyl ether to trigger the displacement of the required triflate. Wender et al. (119) and Kuwujima and co-workers (123) both utilized a halide leaving group, which allowed conversion to the oxetane in good yields of 95% and 86%, respectively, in a single step. A base-mediated cyclization step with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is a common and enduring approach, with Holton et al. (1994), (125, 126) Kuwujima and co-workers (2000), (123) Takahashi and co-workers (2006), (120) and Nakada and co-workers (2015) (129) all using closely related conditions from very similar intermediates (for Nakada’s recent example, see Scheme 7). In all cases the proximity of the required leaving group to the primary alcohol allowed the etherification reaction to proceed in good yield under a variety of conditions. Various synthetic studies have been reported on taxol mimics. (130-132)

Scheme 7. Selected Examples of the Oxetane-Forming Step in Taxol Total Syntheses

In 2009, Fan and co-workers (133) reported oxidative cyclization of malonate Michael adducts with chalcones to selectively access cyclopropanes and oxetane derivatives with high diastereoselectivity (Scheme 8). Cyclization was observed only when iodosobenzene (PhIO) and tetrabutylammonium iodide (Bu₄NI) were utilized. During optimization, cyclopropanes were synthesized in shorter reaction times when alcoholic solvents were used. Conversely, when the reaction was conducted in an open-air system with water, the oxetane was formed as the major product. Substrates bearing electron-rich aryl groups gave improved yields and selectivity for oxetane products, as did addition of SiO₂ and Na₂CO₃.

Scheme 8. Solvent-Controlled Synthesis of Cyclopropanes and Oxetane Derivatives from Michael Adducts of Malonates

Two years later, Yang and co-workers (134) reported a similar iodine-mediated conversion of Michael adducts of malonates with enones to either α-hydroxymalonate derivatives (34), cyclopropanes (35), or oxetanes (36) with high diastereoselectivity (Scheme 9). The oxygen atoms in α-hydroxymalonates 34 and oxetanes 36 were derived from atmospheric O₂, and substoichiometric amounts of I₂ (0.2 equiv) could be used. Each of the three reactions proceeded well when both R₁ and R₂ were aryl groups, with the nature of substituents on the aryl ring having no significant impact on the reaction.

Scheme 9. Selective Synthesis of α-Hydroxymalonates, Cyclopropanes, and Oxetane Derivatives from Michael Adducts

A radical mechanism was proposed that involved initial iodination of the Michael adduct to give key intermediate 37 (Scheme 10). This intermediate could undergo a DBU-mediated cyclization in the absence of O₂, to give cyclopropane 38, or cleavage of the C–I bond and reaction with oxygen and an iodine radical, to give iodoperoxide 39 and then hypoiodide 40. Iodine abstraction with the starting material would give α-hydroxymalonate 41 and regenerate key intermediate 37. Treatment of 41 with I₂ and Na₂CO₃ would give iodide 42, and a simple Williamson etherification would afford oxetane 43. Alternatively, intramolecular electrophilic attack of the hypoiodide would also give iodide 42, with a final C–O bond-forming step.

Scheme 10. Proposed Mechanism for Conversion to Cyclopropane, α-Hydroxymalonate, and Oxetane Products

Recently, Smith and co-workers (135) developed an enantioselective formal [2+2] cycloaddition to form highly substituted, fluorinated β-lactones 44 from fluorinated ketones and α-aroyloxyaldehydes, using chiral N-heterocyclic carbene (NHC) catalyst 47. Reduction to diols 45 with LiBH₄ and activation of the primary alcohol with TrisCl, followed by Williamson etherification, afforded the substituted fluorinated oxetanes 46 with excellent diastereomeric ratio (dr) and ee (Scheme 11).

Scheme 11. Synthesis of Oxetanes via NHC-Catalyzed Formal [2+2] Cycloaddition of Fluorinated Ketones and α-Aroyloxyaldehydes

Following Carreira’s studies on the properties of 3-substituted oxetanes (see section 2), there has been considerable interest in developing approaches to functionalized 3-substituted oxetanes. Carreira’s approach used oxetan-3-one, the chemistry of which is covered in section 5 of this review. Carreira and co-workers (63) developed a four-step synthesis of the cyclic ketone that involved an intramolecular cyclization to form the oxetane (Scheme 12). Dihydroxyacetone dimer 48 was converted into the corresponding dimethylketal 49. Monotosylation with TsCl followed by deprotonation with NaH prompted the intramolecular cyclization, forming oxetane 50. Acidic cleavage of the ketal provided oxetan-3-one 51 in a yield of 62%. This motif has been widely used as a building block to prepare oxetane derivatives and is now commercially available from many suppliers.

Scheme 12. Synthesis of Oxetan-3-one by Intramolecular Cyclization

Use of solid-phase synthesis for preparation of 3,3-disubstituted oxetanes 53 and 55 was reported by Hailes and co-workers (136) in 2005. Polystyrene and a novel PEG 3400 resin were used with a sulfone linker. Polymer-bound precursors were synthesized from polymer-bound sulfonyl chlorides and the desired diols 52 and 54, with bead staining providing evidence for incorporation. Cyclization with sodium hydride proved unsuccessful, but treatment with KOtBu resulted in much improved yields over two steps when compared to solution-based synthesis for both resins and substrates used (Scheme 13a).

Scheme 13. Synthesis of 3,3-Disubstituted Oxetanes from Diols

Vigo et al. (137) reported the synthesis of 3,3-disubstituted oxetanes with hydroxy, amino, and carboxylic acid residues suitable for further functionalization. From diol 56, through a route of cyclization, nucleophilic substitution, and then functional group manipulation, a variety of functionalized oxetanes were prepared (Scheme 13b).

Development of a three-step route from diol 57 via cyclic carbonate 58 allowed access to 3-benzyloxetane 59 in moderate yield (Scheme 13c). (137) Previous cyclization strategies and functional group manipulation had proved unsuccessful for this synthesis.

Further examples of medicinally relevant 3,3-disubstituted oxetanes were reported in 2014 by Boyd and Davies (138) (AstraZeneca). 3,3-Disubstituted oxetanes were synthesized from the relevant substituted dimethyl malonates with installation of a protected hydroxymethyl group, double ester reduction to the diol, tosylation, base-mediated cyclization, and finally removal of the silyl protecting group with tetra-n-butylammonium fluoride (TBAF; Scheme 13d). Yields for the Williamson etherification were reported between 59% and 87%. Scope included various substitution at the 3-position with aryl, allyl, alkyl, and halide substituents tolerated.

Synthesis of a large number of spirocyclic oxetanes has been examined in recent years, often by Williamson etherification in particular incorporating a 3-linked oxetane. An excellent review from Carreira and Fessard (2) on this subject appeared in 2014; we will not replicate their material here but only highlight a small selection of examples. Synthesis and biological testing of an analogue of ciprofloxacin 61 containing a spirocyclic oxetane motif is an excellent demonstration of both the synthetic strategy that has been widely employed for this class of compounds and the potential application of spirocyclic oxetanes in medicinal chemistry. (69, 73) Spirocyclic building block 60 was synthesized in two steps from 3-bromo-2,2-bis(bromomethyl)propan-1-ol (Scheme 14a). Synthesis of ciprofloxacin analogue 61 was achieved in a yield of 68% by use of KOtBu in DMSO at 130 °C (Scheme 14b). Oxetane analogue 61 was then compared against an azetidine analogue and the parent ciprofloxacin in a number of biological assays. Comparable activities were seen for the two spirocyclic analogues, and additionally there was no observable metabolism in human microsomal assays.

Scheme 14. Spirocyclic Building Block 60 and Use in a Ciprofloxacin Analogue

Carreira and co-workers (74) also reported the synthesis of 2-substituted spirocyclic oxetane azetidines (Scheme 15). The addition of furyllithium to azetidine aldehyde 62, synthesized in three steps from tribromopentaerythritol, afforded cyclization precursor 63 with the required 1,3-relationship between the alcohol and electrophilic carbon. Cyclization to the desired spirocyclic oxetane 64 occurred successfully under mild basic conditions (K₂CO₃ in MeOH). This work highlighted how the conditions employed for cyclization can be important in determining the reaction outcome; when KOtBu in THF was used, Grob fragmentation occurred to give 3-exo-methyleneazetidine 65 in a 53% yield. The likelihood of Grob fragmentation occurring appeared to depend on the thermodynamic stability of the olefin formed. Additionally, both the solvent and base utilized have an effect on the probability of Grob fragmentation occurring. (139)

Scheme 15. Preparation of Spirocyclic Oxetane Azetidines

Recently Davis and Bull (140) prepared an unusual bis-spirocyclic oxetane derivative (Scheme 16). Reduction of an oxetane diester to the diol with LiBH₄ proceeded in high yield. Treatment with BuLi and TsCl, followed by a second treatment with BuLi in a separate step, formed the second oxetane ring.

Scheme 16. Preparation of a Bis-spirocyclic Oxetane Derivative

Epoxides have also been used as leaving groups for the synthesis of oxetanes via intramolecular etherification. Kato and co-workers (141, 142) demonstrated the synthesis of oxetanocin analogues involving base-mediated ring opening of cis-epoxides of homoallylic epoxides by KOH to afford oxetanes (61–66% yield) along with the THF product (3.5:1 to 14.5:1 ratio, oxetane/THF). Interestingly, trans- and terminal epoxides gave only the THF product. Additionally, stoichiometric tributyltin methoxide was used by Chung et al. (143) in 1996 for ring opening of a terminal epoxide by a hydroxy group to give 4-[(benzyloxy)methyl]oxetan-2-ylmethanol in 32% yield. Subsequently, Carreira and co-workers (69) used this methodology for synthesis of a bridged bicyclic morpholine; it was also used elsewhere. (144) This disconnection has also been achieved under acidic conditions. In 2002, Birman and Danishefsky (145) first devised this Payne-type rearrangement from the relevant α-epoxide to yield the desired oxetane motif as a last step in the synthesis of merrilactone A. Treatment of α-epoxide 66 with tosic acid in dichloromethane at room temperature yielded merrilactone A with the correct stereochemistry. These conditions have been replicated as the final step in a number of merrilactone A syntheses, yielding approximately 80% in all reports (Scheme 17). (146-150)

Scheme 17. General Procedure for Synthesis of the Oxetane Ring in Merrilactone A via Payne Rearrangement-type Mechanism

3.1.2 Epoxide Ring Opening/Ring Closing

Epoxides can be ring-expanded to oxetanes: as a variant of the Williamson etherification, the cyclization precursor has been accessed by opening an epoxide with nucleophiles bearing leaving groups. In 1980, Servrin and Krief (151) opened epoxides (2-hexyloxirane, 2-hexyl-2-methyloxirane, or 2-methyloxirane) with a selenomethyllithium reagent in THF/HMPT at −78 °C, which was then warmed to 20 °C to afford ring-opened hydroxyselenide 67 (Scheme 18). These intermediates were converted to halides that could be cyclized with a base such as KOtBu or MeMgBr to access the oxetane. Selenoethyl- and selenopropyllithium were also successful to introduce additional Me/Et groups at the oxetane C4 position.

Scheme 18. Oxetane Formation through Epoxide Opening with Selenoalkyllithium

In 1983, Okuma et al. (152) reported a similar method to access the oxetane cyclization precursor by ring opening of epoxides with a sulfoxonium ylide generated in situ from trimethyloxosulfonium iodide. Attack of a 2-substituted or 2,2-disubstituted epoxide with the sulfur ylide accessed the ring-opened intermediate 68, which subsequently cyclized directly in the same reaction flask with release of dimethyl sulfoxide to afford 2-substituted oxetanes in excellent yields of 83–99% (Scheme 19). Aromatic and alkyl substituents were tolerated; however, examples were limited to Ph, p-ClC₆H₅, Me, or H substituents and an example with cyclohexanone.

Scheme 19. Oxetane Formation through Epoxide Opening with Trimethyloxosulfonium Ylide

Okuma et al. (152) demonstrated that by increasing the equivalents of trimethyloxosulfonium iodide, the oxetane motif could be accessed from the corresponding carbonyl compound through initial formation of the epoxide followed by ring opening. A related method was reported that used the sodium anion of an NTs-sulfoximine. (153, 154) Fitton et al. (155) expanded the scope of oxetanes accessed through this method to incorporate alkyl substituents that could be further manipulated to access a range of oxetane derivatives. Treating monosubstituted epoxides with dimethyloxosulfonium methylide resulted in oxetanes 69 in good yields (Table 3). The useful 2-hydroxymethyloxetane motif was formed in 74% yield following acetal deprotection (from entry 1, Table 3), and the vinyl derivatives (entries 2 and 4) successfully underwent bromination with Br₂ or epoxidation with m-CPBA.

Table 3. Expanded Scope of Oxetanes Accessed through Epoxide Ring Opening with Trimethyloxosulfonium Ylide

entry	R	yield (%)
1	CH₂OCH(CH₃)OC₂H₅	70
2	CH₂OCH₂CH═CH₂	65
3	CH₂OC₆H₅	83
4	CH₂CH₂CH═CH₂	56
5	CH(OC₂H₅)₂	59

Fokin and co-workers (156) modeled the ring expansion of an unsubstituted epoxide computationally at the density functional theory MP2 level of theory, utilizing a polarizable continum model to account for solvent effects and determining that formation of the oxetane ring from an epoxide required 13–17 kcal·mol^–1 activation energy; therefore, moderate heating was required. Subsequent ring-expansion barriers were calculated for oxetane to THF at 25 kcal·mol^–1 and THF to tetrahydropyran (THP) at 38 kcal·mol^–1. For 2-methyl- and 2,2-dimethyloxirane, the methylenation of epoxides with dimethylsulfoxonium methylide was modeled and shown to proceed via an S_N2 transition structure and was sensitive to epoxide substitution. Experimental findings were consistent with computational results, whereby enantioenriched chiral oxetanes were accessed from enantioenriched epoxides with full retention of enantiomeric purity (Table 4). 2-Alkyl- and 2,2-dialkylepoxides had similar reactivity when treated with dimethylsulfoxonium methylide; however, the 2,3-disubstituted epoxide was unreactive, resulting in only trace amounts of product (Table 4, entry 5). Consecutive ring expansion was performed, treating chiral oxetanes with dimethylsulfoxonium methylides to form chiral tetrahydrofurans (THFs), also with conservation of ee. Recently, Carreira and co-workers (75) applied this approach to N-Boc-azetidin-3-one, where this transformation was successful in the generation of a spirocyclic azetidine-oxetane. Aggarwal and McGarrigle and co-workers (157) reported the cyclization of a related intermediate to form a 2,2-disubstituted oxetane through conjugate addition of a hydroxy malonate to a vinyl sulfonium salt, forming an ylide, which underwent proton transfer and cyclization.

Table 4. Assessing Chiral Oxetanes from Ring Expansion of Chiral Epoxides with Dimethylsulfoxonium Methylide

entry	R	R¹	R²	R³	conditions	yield (%)	ee (%)
1	C₆H₅	H	H	H	NaH, DMSO, 70 °C	85	>98
2	n-hexyl	H	H	H	t-BuOK, t-BuOH, 80 °C	91	>98
3	H	CH₂OCH₂Ph	H	H	t-BuOK, t-BuOH, 80 °C	80	>98
4	C₆H₅	Et	H	H	NaH, DMSO, 110 °C	88	>98
5	C₆H₅	H	H	Me	t-BuOK, t-BuOH, 120 °C	trace	nd

Shibasaki and co-workers (158) developed a powerful one-pot enantioselective synthesis of 2,2-disubstituted oxetanes involving an asymmetric Corey–Chaykovsky epoxidation reaction, followed by ring expansion of the resulting chiral epoxides to chiral oxetanes. Excellent levels of ee were obtained, with reinforcing enantioinduction leading to partial kinetic resolution and amplified ee. The starting methyl ketone 70 was treated with 1.2 equiv of dimethyloxosulfonium methylide, 5 mol % catalyst 71, and phosphorus oxide additive 72 in the presence of molecular sieves to afford the corresponding chiral epoxide, which was then treated with a further equivalent of the sulfur ylide and 15 mol % catalyst and additive to compensate for the slow reaction rate (Scheme 20). Chiral 2,2-disubstituted oxetanes were accessed in good to excellent yields of 58–88% with up to 99.5% ee, employing both alkyl and aryl methyl ketones. When ethyl ketones such as propiophenone were employed, the epoxide intermediate was produced in 88% ee; however, the subsequent ring expansion provided the oxetane in 91% ee with only a 26% yield, demonstrating that the reaction was sensitive to ketone substitution.

Scheme 20. Asymmetric Synthesis of 2,2-Disubstituted Oxetanes via One-Pot Sequential Addition of Sulfur Ylides to Ketones

3.1.3 Synthesis of Oxetanes from Sugar Derivatives

Saccharides have been used extensively as starting materials for the synthesis of oxetanes, due to the repeating 1,3-functionality and the opportunity to access enantioenriched and diastereomerically defined oxetanes. (159) Similarly, these starting materials have been used in the synthesis of small oxetane-containing natural products, though typically this approach can be lengthy. In this manner, sugars have been used extensively by Fleet and co-workers (160, 161) as starting materials for the synthesis of enantioenriched oxetanes through ring contraction of the triflates of α-hydroxy-γ-lactones (Scheme 21). These were formed from the corresponding α-hydroxy-γ-lactones, which are in turn prepared from compounds derived from sugars. (162-164) Certain nucleophiles attack the lactone carbonyl, leading to ring opening of the lactone, followed by displacement of the triflate to form the oxetane. When lactone 74, derived from glucuronolactone 73, was treated with benzylamine or K₂CO₃ in methanol, ring contraction occurred to form oxetanes 75 and 76, respectively, in good yield. (161)

Scheme 21. Sample Ring Contraction of α-Hydroxy-γ-lactone Triflates

Only one stereoisomer was formed with benzylamine with a yield of 81%, and no reaction was observed when OTf was replaced with OMs. On the other hand, an epimeric mixture was observed when K₂CO₃ in methanol was used (61%, ratio 2:1), with the major product having retention of configuration at the oxetane C2 position due to epimerization prior to oxetane formation. Treatment of ester oxetane 76 with benzylamine and hydrazine hydrate afforded the corresponding amide oxetanes, and reduction was achieved by use of LiAlH₄; both reactions proceeded without epimerization. (161)

The synthesis of an unusual but stable α-chlorooxetane 78 was achieved by Fleet et al. (166) through a Barton modification of the Hunsdiecker reaction (Scheme 22). (165) Ester 76 was converted to the chloride with a yield of 27% through hydrolysis to the sodium carboxylate salt 77, formation of the acid chloride, and reaction with N-hydroxypyridine-2-thione sodium salt under reflux in CCl₄. The structure of this fascinating chlorooxetane was proven by an X-ray crystal structure. (166)

Scheme 22. Synthesis of α-Chlorooxetane 78 through Barton Modification of the Hunsdiecker Reaction

In subsequent work, Fleet et al. (167) showed that α-chlorooxetanes could be converted into oxetane nucleoside analogues through displacement of the chloride with adenine (Scheme 23). A separable 1:1 mixture of C2-epimers 79 and 80 was obtained, which may indicate nucleophilic displacement had significant S_N1 character.

Scheme 23. Synthesis of Oxetane Nucleoside Analogue from α-Chlorooxetane 78

A few years after the reaction with bicyclic lactones, Fleet and co-workers (168) expanded the scope of ring contraction of α-hydroxy-γ-lactones to all four diastereoisomers of 3,5-di-O-benzylpentono-1,4-lactones. These lactones were prepared from 1,2-O-isopropylidinepentofuranose sugars (Scheme 24). Triflates 81–84 were prepared in four steps from the readily available diols of d-xylo, d-ribo, d-arabino, and l-lyxo sugars with yields between 48% and 64%.

Scheme 24. Synthesis of Triflate Lactones 81–84 from Pentofuranose Sugars

Ring contraction was conducted on each example under previously reported conditions (dry K₂CO₃ in anhydrous MeOH), affording methyl oxetane-2-carboxylates 85–88 in yields of 70%–82% (Table 5). Interestingly, for d-xylono and d-arabinono triflates 81 and 83, the expected inversion of configuration occurred, whereas for d-ribono and l-lyxono triflates 82 and 84, retention of configuration at C2 of the lactone resulted. The major product of each ring contraction has a trans relationship between the C2 and C3 substitutents on the oxetane ring. No deuterium incorporation was observed when the reaction was conducted in methanol-d₄, which implied that the stereochemical outcome of these reactions was not a consequence of equilibrium of the oxetane products. Unfavorable interactions during S_N2 ring closure in the open-chain 4-hydroxy-2-O-triflate esters when the substituents of the resulting oxetane are cis-configured were cited as a possible reason for this stereochemical outcome. Epimerization of the hydroxy triflate intermediate therefore occurs more rapidly than cyclization, which favored the trans configuration.

Table 5. Synthesis of Oxetanes 85–88 by Ring Contraction^a

^{Table a}

Inv = inversion of configuration at C2 upon cyclization. ^bRet = retention of configuration upon cyclization.

Fleet and co-workers (169) later demonstrated that ring contraction occurred with C3-deoxy 3-substituted oxetane products (Scheme 25). In this case, inversion of configuration was observed for both d-ribono (89) and d-arabinono (91) substrates upon ring contraction. Yields for 3-alkyloxetanes 90 and 92 were generally lower than those for previously reported 3-ether-substituted oxetanes due to the increased tendency of alkyl triflate lactones to undergo elimination reactions rather than ring contractions.

Scheme 25. Synthesis of 3-Alkyloxetanes 90 and 92

This ring contraction strategy enabled synthesis of the natural product oxetanocin and its α-epimer (Scheme 26). (170) From the triflate lactone, derived from d-xylo 93, ring contraction with K₂CO₃ in MeOH afforded oxetane 94 with inversion of configuration. The epimer of oxetane 94 could be formed from the same triflate lactone in three steps; treatment with sodium trifluoroacetate and MeOH gave the inverted α-hydroxy-γ-lactone (d-arabinonolactone), followed by conversion to the triflate and ring contraction. Radical decarboxylative chlorination gave an unstable α-chlorooxetane, which was immediately trapped as the sulfide with PhSK to be purified. Regeneration of the α-chlorooxetane was conducted with Cl₂ in CHCl₃, followed by addition of benzoyl adenine to give protected adenine oxetane 95 as an epimeric mixture in 23% yield. Separation and subsequent deprotection afforded oxetanocin and α-oxetanocin in 71% and 60% yields, respectively.

Scheme 26. Synthesis of Oxetanocin and Its α-Epimer

Through an almost identical route, Fleet and co-workers (171) synthesized both epimers of norooxetanocin in 15 steps from diacetal glycose. Both α- and β-norooxetanocin were inactive against HIV-1 (up to a concentration of 100 μg·mL^–1). (172) In an improved sequence, epinorooxetanocin was prepared from lactone triflate 96, itself prepared in two steps (Scheme 27). (172) Ring contraction under standard conditions afforded oxetane 97. To access α-chlorooxetane 98, hydrolysis of the ester, followed by treatment with N-chlorosuccinimide (NCS) and lead tetraacetate, gave a single stereoisomer in 58% yield. The chloride was displaced with adenine to give nucleoside oxetane 99 as a single epimer, which was subsequently deprotected with trifluoroacetic acid (TFA), affording epinorooxetanocin with an 80% yield. In vitro studies of epinoroxetanocin showed significant activity against HIV-1 (IC₅₀ = 0.5–1.5 μg·mL^–1), which was similar to the activity of oxetanocin (IC₅₀ = 0.5–1.5 μg·mL^–1).

Scheme 27. Synthesis of Epinoroxetanocin

In 1992, Saksena et al. (173) developed the use of mesylate and tosylate groups for ring contraction under aqueous hydrolytic conditions to form oxetanecarboxylic acids with high yields. Gumina and Chu (174) used the conditions reported by Saksena in their synthesis of the enantiomer of oxetanocin. They achieved this in 16 steps, starting from l-xylose with an overall yield of 2.8%, in a route otherwise similar to that reported by Fleet and co-workers. (170)

Oxetanes constructed by these strategies have provided important building blocks for further functionalization to provide enantioenriched oxetanes with varied substitution patterns, especially at the 3- and 4-position of the oxetane ring. In sections 3.1.3.1 and 3.1.3.2, we report some of the transformations that may be valuable in accessing functionalized oxetane derivatives and for applications in medicinal chemistry.

3.1.3.1 C3 Functionalization and Applications of Oxetanes Derived from Sugars

Fleet and co-workers (175) showed that oxetane 2-esters could undergo a variety of transformations at C3, particularly nucleophilic displacements. Deprotection of the benzyl protecting groups in oxetane 86 proceeded by hydrogenolysis with H₂ and Pd/C with a good yield of 86% (Scheme 28a). After selective silylation of the primary hydroxy group, the secondary alcohol at the C3 position of the oxetane ring could be converted to the triflate with Tf₂O, and triflate 100 could be displaced with inversion by a variety of nucleophiles. Initially this was achieved by use of NaN₃ to form oxetane 101, and no competing elimination reactions were observed. Oxetane 102, prepared from l-rhamnose in four steps, (176, 178) was used to access a range of 3-azidooxetanes 103–105 in a similar manner through reduction of the acetal protecting group, triflate formation, and S_N2 displacement with NaN₃ (Scheme 28b). (177-179) A similar sequence was conducted with d-xylose. (177)

3-Hydroxyoxetane 106 was converted to a single isomer of fluorooxetane 107 through the use of diethylaminosulfur trifluoride (DAST), which proceeded with inversion (Scheme 29). (175) Recently, Wessel and co-workers (86) used DAST in the synthesis of 3-fluorooxetane δ-amino acids as interesting new rigid scaffolds for use in medicinal chemistry. Fleet and co-workers (175) converted fluorooxetane and azidooxetane derivatives to analogues of oxetanocin, and while the azido analogue showed significant antiviral activity against HIV-1 (IC₅₀ = 6 μg·mL^–1), it was less than the activity of oxetanocin itself.

Scheme 29. Synthesis of Fluorooxetane **107** by Use of Diethylaminosulfur Trifluoride

In 1997, Sakya et al. (180) synthesized oxetane-3-thiols from oxetane 108 (Scheme 30). Selective tosylation of the primary alcohol occurred with good yield. This tosyl group could not be displaced by either NaN₃ or amines; instead, retro-aldol and decomposition products were isolated. However, the secondary alcohol could be converted to thiol 109 through triflate formation followed by displacement with KSAc, selective for the secondary triflate, and deprotection.

Scheme 30. Synthesis of Oxetanethiol **109**

These oxetanethiols were subsequently used in synthesis of a variety of oxetane carbapenems 110 and to determine their antibacterial structural activity relationship against both Gram-positive and Gram-negative bacteria (Table 6). The oxetane carbapenems tended to have less activity against Gram-positive bacteria (such as Staphylococcus aureus) compared with the broad-spectrum antibiotic imipenem, (181) but they showed similar activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Oxetane carbapenem 110a was also shown to be more stable to hydrolysis by hog kidney dehydropeptidase (DHP) than imipenem.

Table 6. Structure–Activity Relationships of Oxetane Carbapenems

		minimum inhibitory concn (μg·mL^–1)
organism	strain	imipenem	110a	110b	110c
E. coli	ATCC 25922	0.12	0.25	0.12	0.12
P. aeruginosa	ATCC 27853	2	128	16	64
S. aureus	ATCC 28213	≤0.06	1	0.12	0.12

relative hydrolysis to hog DHP		100	<1

3.1.3.2 C4 Functionalization and Applications of Oxetanes Derived from Sugars

Oxetane derivatives have been developed as isosteres for dipeptides. (182) Toward this aim, Fleet and co-workers (183) incorporated an azide group at the C4 position by two routes: a Mitsunobu reaction with PPh₃, diethyl azodicarboxylate (DEAD), and diphenylphosphorylazide (DPPA) and also a displacement reaction of an alkyl bromide using sodium azide (Scheme 31).

Scheme 31. Synthesis of Alkylazidooxetanes

Toward novel oxetane amino acids, Wessel and co-workers (86, 87) from Roche reported that the azide moiety could be incorporated through displacement of a triflate (Scheme 32). These primary azides were subjected to hydrogenolysis followed by in situ protection with Boc₂O to give protected primary aminooxetane 111 in good yields.

Scheme 32. Synthesis of a Protected Amino Acid Oxetane

Wessel and co-workers (86) achieved hydrolysis of the methyl esters using 1 N LiOH in THF with quantitative yield, and it could also be achieved enzymatically with pig liver esterase (Scheme 33). Acidic aqueous workup led to degradation of oxetane 112; therefore, the reaction was screened in microaqueous reaction systems (organic solvents with a small amount of water added). It was shown that lipase L2 from Candida antarctica provided the best activity, and oxetanecarboxylic acid 112 could be isolated by filtering off the enzyme followed by evaporation of the solvent. This enzymatic hydrolysis was conducted on a gram scale, and an excellent yield was obtained. A related oxetane monomer was incorporated into a β-turn region of cyclodecapeptide gramicidin S, which caused a well-defined cyclic hairpin structure in solution. (184)

Scheme 33. Hydrolysis of Oxetane Ester by Use of *Candida antarctica* Lipase L2

While investigating the preferred secondary structures of homooligomers of oxetane amino acids, (185) oxetane-azido ester scaffolds were converted to β-amino acid monomers and coupled to form a range of β-amino acid oligomers (dimers, tetramers, and hexamers). For example, the δ-2,4-cis-oxetane azido ester scaffold 113 underwent hydrolysis to afford oxetane acid 114. Fleet showed that transesterification to the isopropyl ester allowed for successful hydrogenolysis of the azide to the free amine 115 in good yields. This transesterification avoided intramolecular lactamization and oligomerization, which was observed with hydrogenolysis of methyl ester 113. (186) Treatment of these two monomers with TBTU [N,N,N,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate] gave oxetane dimer 116 in 89% from isopropyl ester oxetane 115. This dimer was subjected to the same iterative process, and homooligomers up to the hexamer were successfully synthesized. Hexamer 117 was built up over five steps with a very good yield of 64% from dimer 116 (Scheme 34). Conformational analysis of these oxetane β-amino acid oligomers by IR and NMR spectroscopy, involving nuclear Overhauser effect (NOE), total correlation (TOCSY), and rotating-frame nuclear Overhauser effect (ROESY) spectra, indicated that well-defined secondary structures were adopted in solution. (185, 187) The major conformation was dictated by an internal 10-membered hydrogen-bonded motif, which is comparable to a conventional α-amino acid peptide β-turn. On the other hand, the trans-oxetane amino acid oligomers did not show any defined secondary structures. By contrast, trans-oxetane amino acid oligomers with a bulky 3-(tert-butyldimethylsilyl)oxy (3-OTBS) substituent did display a defined conformation in chloroform and 2,2,2-trifluoroethanol, enforced through steric interactions without the influence of H-bonding. (188) Cyclic tetrameric derivatives have also been prepared. (189)

Scheme 34. Synthesis of Oxetane Hexamer **117**

Oxetanes have also been incorporated as side chains in β-amino acids for the synthesis and conformational analysis of the foldamers they might adopt in solution. (190) Novel oxetane β³-amino acids 119a,b were prepared from sugar-derived diol 118 in 14 steps with overall yields of 1.4% and 3.7%, respectively (Scheme 35). Oxetane formation was achived via Williamson etherification with NaH in THF. The amine stereocenter was introduced by an aza-Michael addition. Oxetane β³-amino acid 119a was incorporated into tri- and penta-α,β-peptides under standard peptide coupling conditions (191) with l-Ala derivatives. Conformational analysis by NMR, molecular dynamics, and circular dichroism indicated the presence of a well-defined folded conformation that involved hydrogen bonding.

Scheme 35. Synthesis of Novel β³-Amino Acids and Penta-α,β-peptide

3.1.4 Synthesis of Oxetane-Containing Nucleoside Analogues

Nucleoside analogues have been developed as effective classes of novel antiviral and cancer therapeutics. Their mode of action stems from an ability to disrupt nucleotide metabolism and DNA replication, thus leading to apoptosis. (192, 193) Examples include idoxuridine, the first marketed antiviral nucleoside for treatment of herpes simplex virus; (194) zidovudine (AZT), (195) approved in 1987 as a treatment for HIV; and more recently entecavir (196) (approved in 2005) and sofosbuvir (197) (approved in 2013) as treatments for hepatitis B and C, respectively (Figure 13).

Figure 13. Examples of marketed nucleoside antivirals.

Toxic side effects and development of resistance to existing therapies (198, 199) means there has been a continued drive in this area to find novel nucleoside-based therapeutics with optimal physicochemical properties. Several groups in recent years have investigated incorporation of oxetanes, in addition to other functionalities, toward this goal. (200) Wengel and co-workers, (201) in 1998, evaluated the thermal stabilities of duplexes comprising several oxetane-containing modified oligonucleotides (ONs) against the complementary single-stranded DNA and RNA. The synthesis of the desired bicyclic oxetane-containing nucleoside 121 was completed in 12 steps from the known ulose 120 in overall 8.5% yield, with the key cyclization step being intramolecular etherification between the secondary alcohol and primary mesylate group. This was achieved in 93% yield over the mesylation and cyclization steps (Scheme 36). Subsequent steps allowed synthesis of the corresponding 3′-O-phosphoramidite building block 122 for incorporation into ONs.

Scheme 36. Synthesis of Oxetane Nucleoside Phosphoramidite **122** from Ulose **120**

Several modified 14-mer ONs were synthesized along with a 9-mer variant, and the thermal stabilities of their duplexes with single-stranded DNA and RNA were determined by melting-point analysis and compared to that of unmodified ON (Table 7). (201) It was found that the majority of modified 14-mer ONs resulted in decreased thermal stability against both DNA and RNA, with lower melting points being reported. However, 5′-X₁₃T was the notable exception, showing a significant increase in thermal stability against both DNA and RNA (Table 7, entry 7). Additionally, the 9-mer example showed small increases in thermal stability against the reference ON (Table 7, entry 8 vs entry 9), thus demonstrating the potential in incorporating an oxetane into ONs in order to deliver superior physical properties.

Table 7. Melting Point Experiments To Determine Thermal Stability of Modified Oliglionucleotides^a

		T_m (°C)
entry	oligonucleotide	ssDNA duplex	ssRNA duplex
1	5′-T₁₄^b	36.0	34.0
2	5′-T₇XT₆	36.0	33.5
3	5′-T₆X₂T₆	34.5	33.0
4	5′-T₆XTXT₅	35.5	32.5
5	5′-T₅X₄T₅	31.5	37.0
6	5′-T₃(TX)₄T₃	35.5	31.5
7	5′-X₁₃T	58.0	49.0
8	5′-GTGATATGC^b	26.0	26.5
9	5′-GXGAXAXGC	34.5	34.5

Thermal stability is compared to that of the unmodified reference oligonucleotide and is measured at 260 nm in medium-salt buffer: 1 mM ethylenediaminetetraacetic acid (EDTA), 10 mM Na₃PO₄, and 140 mM NaCl, pH 7.2. Concentration of each strand was 2.5 μM. G = 2′-deoxyguanosine monomer; A = 2′-deoxyadenosine monomer; C = 2′-deoxycytidine monomer; T_m = melting point, determined as maximum of the first derivative of absorbance vs temperature curve.

Reference oligonucleotide.

In 2001, Nielsen and co-workers (202) published a study exploring the anti-HIV activity of a conformationally restricted nucleoside analogue of AZT featuring an oxetane motif. Starting from the cheap and readily available d-arabinose, both anomeric configurations of the desired oxetane-containing nucleoside, 124a,b, were synthesized in 12 steps (Scheme 37). A modified Corey–Link reaction furnished an α-azido methyl ester stereoselectively, which was followed by stereoselective reduction of a ketone, ester reduction, and conversion to the mesylate to give oxetane precursors 123a,b. Sodium hydride-mediated etherification delivered the oxetane functionality. However, when the antiviral activity of both anomeric configurations 124a,b was then tested against HIV-1 in MT-4 cell lines, in both cases, no anti-HIV activity was observed at 300 μM.

Scheme 37. Overall Synthetic Strategy for Synthesis of Nucleosides **124a,b**

In 2004, Sharma and Nielsen (203) reported the synthesis of oxetane-containing [3.2.0]bicycloarabinonucleoside 129, of interest for potential in antisense and antigene technology, from alkene 125 (Scheme 38). The key step of the synthesis involved oxidative cleavage of the terminal alkene to give alcohol 126 by use of in situ formed RuO₄ (from RuCl₃·xH₂O and NaIO₄). In the second step of this oxidative cleavage, addition of NaBH₄ reconverted the α-ketol (formed from overoxidation) back to the diol as well as reducing any active Ru species. After protecting group manipulation, thymine was used to displace the acetate at the anomeric center. Deprotection of the benzoyl and acetyl protecting groups followed by mesylation afforded dimesylate 127. Selective hydrolysis of the primary sulfonate ester of the primary mesylate, followed by Williamson etherification, afforded oxetane bicycle 128. Benzyl deprotection gave oxetane 129.

Scheme 38. Synthesis of Bicyclic Oxetane **129** from Sugar-Derived Alkene **125**

Chattopadhyaya and co-workers (204, 205) explored the synthesis and antisense effects of 1′,2′-locked oxetane-containing nucleosides. Extensive studies on the effects of replacing either thymine or cytosine residues in antisense oligonucleotide (AON)–RNA duplexes with nucleoside 130 or 131, respectively, were performed, with a focus on examining the effect on RNase H cleavage (Figure 14). With nucleoside 130, singly, doubly, and triply modified AON–RNA duplexes were found to be similarly good substrates for RNase H as the unmodified duplex. The modified duplexes also exhibited improved protection toward endonuclease, with stability increasing with increasing levels of modification. The modifications led to a loss in thermodynamic stability, which could be improved by introduction of a dipyridophenazine (DPPZ) moiety. (204) For nucleoside 131, singly and doubly modified AON–RNA duplexes were again found to be good substrates for RNase H. Michaelis–Menten kinetics indicated catalytic activity close to that of the native duplex. Target affinity for AON–RNA duplexes modified with nucleoside 131 was significantly improved compared to those modified with nucleoside 130. (205)

Figure 14. Structures of 1′,2′-locked oxetane-containing nucleosides **130** and **131**.

In 2005, Chattopadhyaya and co-workers (206) developed routes to oxetane-containing 1′,2′-locked nucleosides from protected furanose derivatives. The oxetane ring-forming step involved base-mediated Williamson etherification with either a mesyl or tosyl leaving group: for example, the synthesis of uracil derivative 132 is shown in Scheme 39. Synthesis of guanine and adenine derivatives was achieved via a similar strategy, which allowed the synthesis of oxetane-containing nucleosides on a multigram scale. (206) In 2014, Komsta et al. (207) prepared uridine and guanosine 1′,2′-locked oxetane derivatives, with anti-HCV activity; a 1′,2′-oxetane guanosine 6-triphosphate derivative was found to be a modest inhibitor of HCV NS5B polymerase (IC₅₀ = 10 μm).

Scheme 39. Synthesis of 1′,2′-Locked Oxetane Nucleoside

Interest in nucleosides including an oxetane moiety as antivirals for treatment of hepatitis C virus (HCV) has led to a number of studies being published in this area. The synthesis and anti-HCV activity of 3′,4′-oxetane nucleosides was reported by Du and co-workers (208) in 2010. Initially, six examples of the nucleoside with a 4′-hydroxymethyl group were synthesized (133–137), with varying groups known to be compatible with anti-HCV activity at the 2′-position. Synthesis of the cytosine-based analogues was achieved in 12 steps from the corresponding uridine nucleosides (Scheme 40a), whereas the adenine example 138 was synthesized in 10 steps directly from 2′-deoxy-2′-β-fluoroadenosine (Scheme 40b). In both cases, the key ring-forming cyclization was a base-mediated displacement of a triflate (Scheme 40a) or a cyclic sulfate group (Scheme 40b).

Scheme 40. Synthesis of Cytosine and Adenine Oxetane-Containing Nucleoside Analogues

When subjected to the subgenomic replicon assay, none of the oxetane derivatives showed significant antiviral activity compared to several related non-oxetane-containing analogues. This lack of activity was postulated to be due to an inability of the modified nucleosides to be anabolized to the triphosphate derivative, an essential step for antiviral efficacy. Therefore, the triphosphate derivatives of 134–136 were prepared and their activity relating to inhibition of HCV polymerase (NS5B) was explored and compared to that of a known inhibitor, PSI-6130. In this case, inhibition of HCV polymerase was observed, albeit at higher concentrations than PSI-6130 (Table 8), (208) demonstrating that phosphorylation might be the inhibiting factor for activity in whole-cell replicon studies.

Table 8. Inhibition of HCV Polymerase (NS5B) Activity in Vitro by Oxetane-Containing Triphosphate Nucleosides Compared to Known Inhibitor PSI-6130

nucleoside	IC₅₀ (μM)
139	30.96 ± 4.75
140	78.91 ± 5.68
141	32.76 ± 5.36
PSI-6130	5.37 ± 0.50

In 2014, both Du et al. (209) and Jonckers et al. (210) published anti-HCV data for nucleosides furnished with a pendant oxetane group at the 2′-position. The study by Jonckers et al. (210) indicated disappointing results for 4′-hydroxymethyl derivatives 142–144, as significantly reduced inhibition of HCV replication was seen compared to other derivatives in a luciferase assay in Huh-7 replicon cells (Table 9).

Table 9. Selected Results Comparing the Anti-HCV Activity of Oxetane-Containing Nucleoside Derivatives to That of a Cyclopropane Analogue

nucleoside	EC₅₀ (μM)
142	>98
143	17.1
144	7.3

In a similar study by Du et al., (209) several 2′-oxetane derivatives were compared, unfavorably, to the 2′-tetrahydrofuran derivatives in a luciferase-based genotype 1b replicon assay in Lunet cells (Table 10). Only one example, 143, indicated any anti-HCV activity, and this was significantly lower than the best 2′-tetrahydrofuran example. In the two studies, different anti-HCV activities were calculated for nucleoside 143; this was likely due to the different assays used in the studies.

Table 10. Anti-HCV Activity of Pyrimidine Nucleosides

In both studies, by Du et al. (209) and Jonckers et al., (210) a prodrug strategy was successfully exploited to bypass the restrictive phosphorylation steps. In the study by Jonckers et al., (210) 25 phosphoramidate derivatives were prepared from the 4′-hydroxymethyl derivative, by use of N-methylimidazole (Scheme 41). The anti-HCV activity of each compound was investigated, and generally very promising EC₅₀ values in the low micromolar range were observed. Additionally, cytotoxicity up to a 98 μM concentration was observed in only one compound.

Scheme 41. Synthesis of Oxetane-Containing Nucleoside Prodrugs

Du et al. (209) also prepared a number of prodrug derivatives 151 and 152 (via an analogous method to that shown in Scheme 41) with similarly positive results against a HCV replicon assay using ET-Lunet cells (Table 11). Once again, no cytotoxicity was observed up to concentrations of 100 μM. As with the 2010 study of Du and co-workers, (208) triphosphate derivatives 153 and 154 were also prepared. These examples demonstrated more promising results than the corresponding tetrahydrofuran-containing analogues and the 4′-hydroxymethyl derivatives against NS5B polymerase and its S282T mutant (Table 12). (209)

Table 11. Anti-HCV Activity Data for Prodrug Nucleoside Analogues^a

^{Table a}

Studied by Du et al. (209).

Table 12. Anti-HCV Activity Data for Triphosphate-Containing Nucleosides

Prasad and co-workers (211) identified oxetanoribonucleosides as potentially interesting antiviral agents, and in 2014 they developed a synthesis of C-4′-spiro-oxetanoribonucleosides utilizing a diastereoselective Novozyme-435-catalyzed deacylation step. In just seven moderate- to high-yielding steps, both thymine and uracil spironucleoside derivatives 155 and 156 could be formed (Scheme 42).

Scheme 42. Seven-Step Synthesis of C-4′-Spiro-oxetanoribonucleosides **155** and **156**

3.1.5 Oxetane Synthesis through Electrophilic Halocyclization of Alcohols

Intramolecular haloetherification has been shown to be a viable strategy for the synthesis of oxetanes but has received relatively little investigation. Throughout the 1980s and early 1990s, a variety of 4-exo-trig electrophilic cyclizations to form oxetanes were discovered largely by use of N-bromosuccinimide (NBS) and often with constrained structures. In 1980, Ehlinger and Magnus (212) found that vinyl silane 157 favored an exo cyclization process, giving adamantyloxetane 158 in a very good yield of 92% (Scheme 43). The THF that would result from endo cyclization, the desired product in this study, was not observed. A few years later, in the process of determining the stereochemistry of cis-clerodane diterpenes, Manabe and Nishino (213) formed oxetane 159 in quantitative yield by use of NBS (Scheme 44). The same reaction was used by Paquette et al. (214) in the synthesis of a [5.9.5] tricyclic system closely related to jatrophatrione.

Scheme 43. Synthesis of Adamantyloxetane through NBS-Mediated 4-exo-trig Cyclization

Scheme 44. Synthesis of Oxetane-Containing Diterpene Derivative

In the late 1980s, bis(sym-collidine)iodine perchlorate [I(coll)₂ClO₄] reagent was used to synthesize β-iodooxetanes by a 4-exo-trig cyclization. (215) This reagent, which was generated in situ from iodine and bis(sym-collidine)silver(I) perchlorate, could provide three- to seven-membered ring ethers by use of unsaturated alcohols. Four oxetane examples were demonstrated, which indicated that tertiary alcohols helped the exo cyclization, though relatively high yields were also achieved if the double bond was substituted (Scheme 45). The methyl group altered the charge distribution on the iodonium intermediate, which made it more electrophilic at the C3 position. Finally, when an unsubstituted unsaturated alcohol was used, an inseparable 1:1 mixture of oxetane and THF was observed (no yield given). Stepan et al. (82) used this approach to develop the γ-secretase inhibitors discussed in section 2. Oxetane 161 was formed from alcohol precursor 160, and the crude material was used to form the alkylated sulfonamide products, obtained in low yields (Scheme 46).

Scheme 45. Synthesis of Iodo-Substituted 2-Alkyloxetanes via 4-exo-trig Cyclization

Scheme 46. Synthesis of γ-Secretase Inhibitor **162** via Iodonium-Mediated Oxetane Cyclization

Jung and Nichols (216) used this 4-exo-trig haloetherification cyclization strategy to synthesize racemic oxetanocin A analogues, predicting that the aryl and vinyl groups on the alcohol substrate 163 would be enough to promote oxetane formation. Cyclization from alcohols 163a–c occurred via in situ formation of bis(collidine)iodine(I) perchlorate from the silver salt to afford good yields and selectivity (oxetane/THF) for each substrate (Scheme 47). Trans-substituted oxetanes 164 were the major products, as determined by NOESY experiments, but reductive deiodination of 164a with LiAlH₄ indicated that all four possible isomeric oxetane products formed in a ratio of 10:2:1.5:1. Oxetanes 164 and the respective THFs 165 could be separated after displacement of the alkyl iodide with acetate; ozonolysis followed by reduction gave oxetanocin A analogues.

Scheme 47. Accessing Oxetanocin A Analogues via Iodonium-Mediated Oxetane Cyclization

In 1997, an asymmetric variant of this process was achieved through incorporation of an oxazolidinone auxiliary. (217) With the Evans auxiliary a variety of substituted alcohols underwent the cyclization successfully, and only oxetane products 166 were observed. However, the oxetane bearing a phenyl group readily decomposed (Table 13). Interestingly in a previous study, use of methyl esters preferentially gave THF products. (218) Good facial selectivity was observed in the cyclization step, proposed to be due to minimizing a 1,3-transannular interaction between the iodomethyl and R groups in the developing oxetane ring. The selectivity went down as the size of R increased, suggesting the transition state to the major product may experience allylic strain (A^1,3 strain) between the terminal vinyl hydrogen and imide group (Scheme 48).

Table 13. Iodine-Mediated Cyclization of Enantioenriched Oxetanes through Incorporation of an Evans Auxillary

entry	R	yield 166 (%)	ratio a:b
1	Me	63	>98:<2
2	Et	90	82:18
3	iPr	77	81:19
4	Ph	85	^a

Decomposition occurred in this case.

Scheme 48. Possible Transition States Explaining the Facial Selectivity of Cyclization

Exo cyclization of vinylsilanes was later investigated by Rousseau and co-workers (219) (Scheme 49). The nature of the counterion in the halide reagent was important, with best results obtained with hexafluoroantimonate. Tertiary alcohols that were unsubstituted on the double bond gave only one diastereoisomer (167a) upon reaction with the bromonium reagent Br(coll)₂SbF₆, and Z- and E-alkenes gave different oxetane diastereoisomers. When secondary alcohols were used, mixtures of cis- and trans-2,4-disubstituted oxetane isomers were obtained (167b). Substituents on the C═C double bond led to mixtures of diastereomers (167c), which could not be identified. Finally, reactivity of the iodonium salt, I(coll)₂SbF₆, was investigated but a reduced yield was obtained (167d).

Scheme 49. Electrophilic Halocyclization of Functionalized Vinylsilanes

Similar transformations have been reported by exo cyclization using electrophilic S and Se reagents to generate oxetanes. The electrophilic addition of PhSe, by use of PhSCl, and etherification was first reported as an unwanted side reaction in the synthesis of a cis-hydrindenone, a bicyclic natural product scaffold. (220) Arjona et al. (221) shortly afterward reported electrophilic addition using both PhSCl and PhSeCl with a variety of 7-oxanorbornenic substrates. The use of PhSCl was more effective at promoting etherification and gave oxetane 168a as the major product, whereas the use of PhSeCl gave the addition of chloride as the major product. Improved selectivity and yields for the oxetanes could be achieved if the temperature of the reaction was lowered, though tertiary alcohols were required to gain high yields for cyclization (Table 14). (222)

Table 14. Investigations into Electrophilic Cyclization of a 7-Oxanorbornenic Substrate

entry	electrophile (EX)	solvent	temp (°C)	yield 168 (%)	ratio a:b
1	PhSCl	CHCl₃	rt		4:1
2	PhSCl	CH₂Cl₂	–50	93	1:0
3	PhSeCl	CHCl₃	rt		1:4
4	PhSeCl	CH₂Cl₂	–78	84	9:1

Synthesis of four-membered rings from a 4-endo-trig cyclization is much less common than a 4-exo-trig cyclization, due to the strain in the transition state. However, Homsi and Rousseau (223) showed that oxetanes (as well as other four-membered rings) could be synthesized in reasonable yields from cinnamic alcohols through a 4-endo-trig cyclization by use of bis(collidine)bromine(I) hexafluorophosphate (Scheme 50a). The E- and Z-alkenes gave the same oxetane, with the stereochemistry determined to be trans due to a coupling constant of 6 Hz (expected to be larger for cis).

Scheme 50. Oxetane Synthesis via 4-endo-trig Haloelectrophilic Cyclization^a

Examination of the influence of substituents on cyclization revealed that primary and secondary alcohols mainly gave low yields of oxetanes and significant degradation, and tertiary alcohols gave oxetanes in good yields (Scheme 50b). (223, 224) A tertiary alcohol with an α-phenyl group led to oxetane formation in moderate yield (55%). When R ≠ R′, mixtures of diastereoisomers were observed. These oxetanes were further functionalized in order to access oxetin derivatives, for example, through oxidative cleavage of the phenyl group with NaIO₄ and catalytic RuCl₃ (not shown).

3.1.6 Other C–O Bond-Forming Cyclization Approaches

In 2014, Dussault and co-workers (225) reported the synthesis of cyclic ethers through a C–O bond formation with reversed polarity. Unlike the traditional Williamson etherification (oxyanion and electrophilic carbon), carbanions as enolate anions and electrophilic oxygen in the form of a peroxide were used. Cyclization proceeded rapidly in the presence of KOtBu or KH in THF, giving oxetanes, THFs, and tetrahydropyrans (THPs) in high yields (Scheme 51a). The transformation was also achieved in an intermolecular fashion with t-butyl iodoalkyl peroxides and cyclohexanone to give the spirocyclic ether derivatives (Scheme 51b).

Scheme 51. Synthesis of Oxetane, Tetrahydrofuran, and Tetrahydropyran Rings through Reverse C–O Bond Formation

Commonly, oxetan-3-ones have been formed by intramolecular OH insertion of diazo compounds, which has been previously reviewed. (5, 226) In 2010, Zhang and co-workers (227) reported an alternative, whereby a gold carbene was generated from an alkyne that formed oxetan-3-ones from propargylic alcohols in one step, with Au(I) as catalyst (Scheme 52). Functionalized secondary and tertiary propargylic alcohols were successfully employed though they required a slight modification to the catalyst and pyridine N-oxide additives.

Scheme 52. Au(I)-Catalyzed Cyclization of Propargylic Alcohols to Oxetan-3-ones

Sharma and Williams (228) demonstrated the formation of oxetan-3-ones in a two-step sequence from allenes (Scheme 53). Double epoxidation of the allene and then halide or thermally induced rearrangement of the spirodiepoxide gave the desired oxetan-3-one analogues. Different conditions for the rearrangement gave different diastereomers as the major product.

Scheme 53. Synthesis of Oxetan-3-ones in Two Steps from Allenes

3.2 Cyclization through C–C Bond Formation

The formation of oxetanes via C–C bond formation is relatively unexplored, but there are increasing examples of this as an effective and complementary strategy. In the 1990s, Craig et al. (229, 230) reported the use of a C–C bond-forming cyclization for the stereoselective synthesis of bicyclic ketooxetanes 170 and 172 by intramolecular C-glycosidation (Scheme 54). Silver triflate mediated the cyclization of thiopyridyl glycosides 169 and 171 in moderate yields through addition of the silyl enol ether side chains to the generated oxocarbenium intermediate. The stereoselectivity was rationalized as resulting from minimization of unfavorable steric interactions between the bulky nucleophilic side chain and the ring system in the transition state. Extension of this methodology to more complex bicyclic systems from sugar derivatives was achieved by variation of the leaving group and cationic activator, either under the original conditions or with thiophenyl glycosides with tin chloride or ethylaluminium dichloride. (231, 232)

Scheme 54. Intramolecular C-Glycosidation Route to Oxetanes

Intramolecular cyclization with epoxide opening through C–C bond formation has been used to form oxetanes. First reported in 1976 by Still, (233) trans-epoxy allylic ether 173 was treated with sBuLi in THF/hexamethylphosphoramide (HMPA) at −78 °C to form vinyl oxetane 174 regioselectively, via stereospecific cyclization of the resulting allyloxycarbanion (Scheme 55). Formation of the more strained four-membered ring over the isomeric five- or six-membered rings was favored due to the lower strain necessary in the transition state to obtain the required alignment of the carbanionic center and the epoxide C–O bond. The trans isomer of 173 was required for intramolecular epoxide ring opening: when the cis isomer was treated with sBuLi, 2-cyclohexenol was formed. The addition of 4% HMPA was required to prevent the oxetane ring opening of 174 through further reaction with sBuLi.

Scheme 55. Vinyl Oxetane Formation via Intramolecular Epoxide Ring-Opening Cyclization

Bird and Hormozi (234) reported a similar outcome upon treating allyl glycidyl ethers with sBuLi in THF/HMPA at −78 °C; the four-membered oxetane or seven-membered oxepane products were favored over the isomeric THF or THP. In general, the oxepane product was favored, but two examples gave the oxetane as the major product due to substitutent effects. In 1983, Williams and Grote (235) reported the intramolecular epoxide ring opening of substrates bearing a benzyl substituent to afford various cyclic ethers. For oxetane examples, treatment of epoxides with 3 equiv of lithio-2,4-dimethylpiperidide (LiDMP) and 3 equiv of HMPA in THF at −78 °C, followed by warming to 22 °C for 2 h, resulted in cyclization (Scheme 56). Good stereocontrol was observed, with the phenyl ring preferring orientations that minimized unfavorable steric interactions.

Scheme 56. Intramolecular Cyclization of Epoxy Ethers Bearing a Benzyl Substituent

Mordini et al. (236) further explored the reactivity of benzyl epoxides as precursors to access oxetanes by treating benzyl epoxy ethers with 2 equiv of LiDAKOR (lithium diisopropylamine and potassium tert-butoxide) in THF at −50 °C for 15 h. Cyclization of the benzylic anion by attack at the epoxide formed 2,3-disubstituted oxetanes with complete anti selectivity between the C2 and C3 substituents, but yields were low due to a competing elimination reaction to form vinyl ethers 176 (Scheme 57a). The electronics of the aryl group were important in determining reaction outcomes. With electron-rich examples, migration of the lithiated anion from the benzylic position occurred, resulting in formation of the vinyl ether product (Y = OMe, Me, and tBu). Electron-withdrawing substituents favored oxetane formation unless the anion was too stable; the p-nitro substituent gave no reaction. When a phenyl ring was present (Y = H), the oxetane could be accessed as the only product in 70% yield. When benzyloxy ether 177 was treated with LiDAKOR and a large excess of nBuLi at higher temperature (25 °C), Z-alkene diol 178 was formed due to further reaction with excess base (Scheme 57b). (237) The lithiated oxetane underwent ring opening to form a carbene intermediate, which, following an alkyl 1,2-shift, afforded the observed diol. The same process was reported for more functionalized alkoxymethyl derivatives; all substrates cleanly converted to the oxetanes in good yields of 50–75% upon treatment of the epoxides with LiDAKOR. (238) Subsequent treatment with nBuLi (4 equiv) resulted in diol formation with stereocontrol.

Scheme 57. Oxetane Formation from Cyclization of Benzyl Epoxides

α-Substituted epoxy ethers 179 prohibited migration of the anion, resulting in trisubstituted oxetanes 180 as the sole products. (239) Treating benzyloxy epoxides, prepared by a Sharpless kinetic resolution, with LiDAKOR or LiCKOR (butyllithium and potassium tert-butoxide) in THF at −50 °C resulted in excellent yields of the trisubstituted oxetanes (Table 15, entry 1).

Table 15. Stereoselective Synthesis of Trisubstituted Oxetane through Intramolecular Epoxide Ring Opening

entry	Y	2,3-syn:2,3-anti	yield 180 (%)
1	C₆H₅	13:87	80
2	p-F–C₆H₅	12:88	81
3	CH₂═CH	2:98	80
4	C₆H₅S	78:22	86

In 1997, Mordini et al. (240) expanded these studies to access amino alcohols bearing an oxetane moiety. Benzyl epoxy ethers derived from valine, leucine, and serine were treated with LiDAKOR at −50 °C to generate the amino alcohol-substituted oxetanes (Scheme 58). Employing the E isomers of 181 resulted in formation of the anti configuration of oxetane 182. However, when a Z isomer of the benzyl epoxy ether derived from serine was employed (protected as an oxazolidine), the oxetane was formed in 65% yield and a mixture of syn and anti (30:70) configurations was observed.

Scheme 58. Regio- and Stereoselective Synthesis of Amino Alcohol-Substituted Oxetanes

Trisubstituted oxetanes with a hydroxymethyl substituent could be generated from monosubstituted epoxides. Terminal epoxy α-substituted ethers 183, upon treatment with LiCKOR or LiDAKOR at −50 °C, afforded 184 (Table 16). (241) When Y was a phenyl ring or an alkyne, 2-phenyl- or 2-alkynyloxetanes were the major products, demonstrating preferred formation of the four-membered ring over the isomeric THF. The relative stereochemistry of the oxetane products at C2/C3 was determined by consideration of the stereochemistry of epoxy ether substrates and selectivity for the anti configuration of Y and hydroxymethyl substituents (Table 16, entries 1–4). Oxepanes 185 were formed instead when allyl epoxy ethers were employed (Table 16, entries 5–7). Enantioenriched cis-substituted epoxides were also converted to enantioenriched epoxides. (242) A synthesis of oxetanocin used this strategy with lithiation of allyl ether and epoxide opening; however, selectivity and yield for the desired oxetane were low. (243, 244)

Table 16. Stereoselective Synthesis of Hydroxyoxetanes through Cyclization of Epoxy Ethers

entry	R	Y	184 (syn/anti):185 (syn/anti)	yield (%)
1	C₅H₁₁	C₆H₅	98 (5/95):2	53
2	CH₂OSiMe₂tBu	C₆H₅	98 (2/98):2	55
3	C₅H₁₁	CH≡C	98 (20/80):2	55
4	CH₂OSiMe₂tBu	CH≡C	98 (15/85):2	50
5	H	CH₂═CH	2:98 (98/2)	45
6	C₅H₁₁	CH₂═CH	2:98 (98/2)	65
7	CH₂OSiMe₂tBu	CH₂═CH	2:98 (98/2)	53

Fujioka and co-workers (245) developed a C–C bond-forming route to highly substituted 2-phosphonatooxetan-3-ones by intramolecular ester condensation (Scheme 59). Cyclization precursors such as 186 were prepared from the corresponding methoxymethyl ether with trimethylsilyl triflate (TMSOTf) and P(OMe)₃, and the cyclization was then promoted with lithium diisopropylamide (LDA) in the presence of tetramethylethylenediamine (TMEDA) to form oxetanone 187. The phosphonates could then be used in Horner–Wadsworth–Emmons reactions to generate the substituted exo-methyleneoxetane 188. A one-pot process gave similar yields to the two-step procedure.

Scheme 59. Synthesis of Oxetan-3-ones by Intramolecular Ester Condensation

In 2014, Bull and co-workers (246) reported an anionic substitution cyclization reaction to form 2-functionalized oxetanes, forming the C2–C3 bond. 2-Sulfonyl oxetanes were targeted as unusual fragments for fragment-based drug discovery but presented unsuitable substrates for C–O bond-forming cyclization approaches. (85) This prompted more extensive investigation of a C–C bond-forming approach. The required cyclization precursors 189 were accessed in three steps from readily available chloromethyl aryl sulfides. Treatment of aryl sulfones 189 with lithium bis(trimethylsilyl)amide (LiHMDS) resulted in formation of a carbanion, stabilized by the sulfone, which effected cyclization to afford 2-sulfonyl oxetane 190 (Scheme 60). The reaction proceeded in high yield in just 1 h at 0 °C and was successful on a gram scale. The aryl group could be readily varied to build a collection of 2-sulfonyl oxetanes. The sulfonyl oxetane fragments were further derivatized through deprotonation on the ring, aided by the sulfonyl group (section 6), as well as cross-coupling reactions through the aryl substituent, maintaining the oxetane ring intact. (246, 85) Furthermore, the chemical and metabolic stability of the fragments, relevant to fragment-based drug discovery, was assessed. (85) This approach to oxetane synthesis was extended to sulfinyl oxetanes, which cyclized under modified conditions upon deprotonation adjacent to the sulfoxide. (247)

Scheme 60. Synthesis of 2-Sulfonyl Oxetanes

The C–C bond-forming strategy was extended to a two-step approach to 2,2-disubstituted oxetane derivatives. (140, 248) A rhodium acetate catalyzed O–H insertion between ethyl diazomalonate and β-bromohydrins rapidly constructed suitable cyclization precursors 191 (Scheme 61). Cyclization forming the C–C bond [NaH in N,N-dimethylformamide (DMF) at 0 °C for 1 h] was very effective to generate 2,2-disubstituted oxetanes 192. Substituents were incorporated at the 4-position by use of substituted bromohydrins, and the ee of enantioenriched bromohydrins was transferred to the oxetane product. Varied substituents could be incorporated at the 4-position, and chlorides were also effective as leaving groups. More highly substituted oxetane examples were prepared from tertiary alcohols and 1,2-substituted bromohydrins, including cyclic systems to generate fused oxetanes. These diester oxetane derivatives were further elaborated in order to generate a range of oxetane-containing fragments and building blocks.

Scheme 61. Oxetane Synthesis by O–H Insertion/C–C Bond-Forming Cyclization

The use of other diazo compounds gave a series of novel functionalized oxetane motifs. From the corresponding diazo compounds, varied functional groups were introduced into the oxetane products, including amides, nitriles, phosphonates, and sulfones (Scheme 62). (249) More substituted examples were also demonstrated, with low to good diastereoselectivity. Through the use of donor–acceptor diazo compounds, aryl rings could also be introduced onto the oxetane ring. With these examples, deprotonation with LiHMDS in THF gave better conversions. Ester hydrolysis was again demostrated, and amide coupling with nitrile- and aryl-substituted examples accessed new amide derivatives.

Scheme 62. Synthesis of Functionalized Oxetanes from Unsymmetrical Diazo Compounds

4 [2+2] and Formal [2+2] Cycloadditions

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This section will consider recent examples in the synthesis of oxetanes where both the C–C and C–O bonds are formed in a single operation. Given the comprehensive reviews in recent years on the topic of the Paternò–Büchi reaction, (3, 4, 250-252) here selected examples of photochemical [2+2] reactions will be presented, including continuous-flow approaches and other formal [2+2] reactions, focusing on recent advances. See section 7 for examples of [2+2] reactions involving allenes to form 2-alkylideneoxetanes.

4.1 Paternò–Büchi [2+2] Photocycloaddition

Over many years, the light-induced Paternò–Büchi reaction between carbonyls and olefins has been exploited for oxetane synthesis. High yields are often achieved for suitable substrates, frequently affording highly substituted oxetanes. Reaction between the alkene and a photoexcited singlet or triplet carbonyl derivative proceeds to the oxetane by either a nonconcerted or concerted pathway. Where the reaction occurs through the triplet-state carbonyl, the reaction is nonconcerted and proceeds through a C,C-biradical intermediate, first forming the C–O bond. However, reaction of the singlet carbonyl is more complex and can occur through either a concerted mechanism or nonconcerted mechanism. (3, 4, 253-256) While regio-, site-, and stereoselectivity can be challenging, such selectivities have been achieved, for example, in the extensive work by Bach et al., targeting 3-silyloxy (257, 258) and 3-aminooxetane derivatives (259-263) (Scheme 63). (264, 265) In this work, reactions were conducted by irradiating aryl aldehydes and silyl enols or N-acyl enamines with ultraviolet light, and high diastereoselectivity was obtained, with a cis configuration favored between the aryl group and the silyl ether/amine.

Scheme 63. Synthesis of (a) 3-Silyloxyoxetanes and (b) 3-Aminooxetanes via Paternò–Büchi Photochemical [2+2] Cycloadditions

Recently, Griesbeck et al. (266) have formed fused oxetaneisoxazolines by a Paternò–Büchi reaction of methyl-substituted isoxazoles with aryl aldehydes with high regioselectivity and exo diastereoselectivity. Zhang and co-workers (267) reported the [2+2] cycloaddition reaction of oxazoles with isoquinoline-1,3,4-trione to form spiroisoquinolineoxetanes, which underwent an acid-catalyzed hydrolysis to give spiroisoquinolineoxazoline products. Furthermore, the Paternò–Büchi reaction has been conducted on designed chiral templates with dihydropyridones, (268, 269) with 8-phenylmenthol as an auxiliary, (270) and directed by chiral hydroxy groups. (271) Additionally, the synthesis of a variety of natural products, for example, oxetanocin (272) and merrilactone A, (273) successfully utilized the Paternò–Büchi reaction as the oxetane-forming step.

There are certain substitution patterns around oxetanes that have only been prepared through [2+2] approaches, one such example being 3,3-diaryl-substituted oxetanes. In 2001, Xu and co-workers (274) reported the synthesis of a 3,3-diphenyloxetane in 98% yield by a Paternò–Büchi reaction (Scheme 64). Prior to this work 3,3-diaryloxetanes were not known in the literature.

Scheme 64. Synthesis of 3,3-Diphenyloxetane by Paternò–Büchi Reaction

Subsequently, Inoue and co-workers (275, 276) used [2+2] photocycloaddition methods for the synthesis of 3,3-diphenyloxetanes from chiral cyanobenzoates and diphenylethene. Interestingly, the diastereoselectivity was entirely dependent on the mode of excitation (direct excitation of acceptor or selective activation of the charge-transfer band). Nonintercovertible diastereomeric pairs of excited-state complexes were generated with different ratios depending on excitation, and the dr was carried through to the oxetane products. The mode of excitation was controlled by simply changing the irradiation wavelength. (275, 276)

D’Auria and co-workers (277) examined the Paternò–Büchi reaction with alkenyl boronates and benzophenone. When pinacol boronate 193 and benzophenone were irradiated in benzene at 310 nm, the product oxetane 194 was observed in a 30% yield (Scheme 65a). Interestingly, when the N-methyliminodiacetic acid (MIDA) boronate derivative 196 was submitted to the same conditions, allylic alcohol 197 was observed in 66% yield, resulting from hydrogen abstraction at the allylic position (Scheme 65b). Computational studies indicated that the Paternò–Büchi reaction was likely to proceed via C,C-biradical intermediate 195. This differed from the previous hypothesis that electron-poor alkenes proceeded mainly by a C,O biradical intermediate. Further computational studies suggested that both observed products were the kinetically favored products and not thermodynamically preferred. (277)

Scheme 65. Photochemical Reactions of Electron-Poor Alkenyl Boronates with Benzophenone

Photochemical reactions, although often powerful as a synthetic tool, may involve long irradiation times that can lead to reduced yields of the product due to undesired reactions over the extended time period. In recent years, reactions in continuous flow have been described as a strategy to achieve more efficient and uniform irradiation. (278) The first example of a [2+2] cycloaddition in a microflow system was published in 2004; enones and vinyl ethers were reacted to give the corresponding cyclobutane, by use of a 300 W mercury lamp and a residence time between 2 and 3.2 h. (279) The equivalent reaction on a model substrate in a batch process gave a significantly lower yield (8% vs 88%), demonstrating the potential of this approach. (279) Subsequently, this methodology has been applied to the Paternò–Büchi reaction for synthesis of oxetanes. In 2011, Ryu and co-workers (280) demonstrated that using either a 15 W black light (BL) or a 300 W mercury lamp in a microflow photoreactor system with a residence time of 1.2 or 4 h converted benzophenone and prenyl alcohol to the desired oxetane in excellent yields of 84% or 91% (Scheme 66). The 15 W black light required an extended residence time to achieve comparable yields, but the energy efficiency was still far superior to the batch process, which yielded only 51% of product after 92 h. (280)

Scheme 66. First Example of Paternò–Büchi Cycloaddition in Flow

A single example of a Paternò–Büchi cycloaddition in flow was published by Booker-Milburn and co-workers (281) in 2014 (Scheme 67). After 3 h, the batch process (run at a 0.3 M concentration) gave 14.05 g of product (67% yield). Under optimized flow conditions at a flow rate of 3 mL·min^–1, 20.52 g of product was isolated after 3 h (72% yield), representing an increase in productivity of 50%.

Scheme 67. Example of Paternò–Büchi Cycloaddition in Flow Compared to Batch Process^a

In 2014, Kakiuchi and co-workers (282) investigated the Paternò–Büchi reaction, using slug flow technology to increase the efficiency of the system, which involves two interspersed phases in the flow microsystem. Three different modes of flow were investigated and compared to batch reaction: normal flow, slug flow with substrate solution/N₂, and slug flow with substrate solution/H₂O. Both normal flow and slug flow approaches gave a considerable increase in reaction efficiency compared to the batch reaction (Table 17). (282) The slug flow approach with substrate solution/H₂O combination gave the highest efficiency. Suggested reasons for the increase in efficiency include light dispersion effects and a stirring effect caused by movement of the second layer, as well as a thin-layer effect leading to a short pathway for irradiation. All conditions gave the same diastereoselectivity.

Table 17. Effect of Normal and Slug Flow Conditions on Efficiency of Paternò–Büchi Cyclization

			energy efficiencies
reactor	yield (%)	irradiation time (s)	%·W^–1·h^–1	%·W^–1·h^–1·cm^–2
batch	40	180	1.60	0.561
normal flow	39	30	9.36	0.596
slug flow^a	45	15	21.6	1.376

Using H₂O and substrate solution.

4.2 Formal [2+2] Cycloadditions

In 2011, Mikami et al. (283) reported a Lewis acid-catalyzed asymmetric formal [2+2] cycloaddition to form 2-trifluoromethyloxetanes from trifluoropyruvate and activated alkenes (Scheme 68). This transformation was achieved by use of either Cu(II) or Pd(II) complexes depending on the vinyl substrate: silyl ethers required Cu–bis(oxazoline) complex A, whereas Pd–BINAP complex B [BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] was required for the less reactive vinyl acetate.

Scheme 68. Synthesis of 2-Trifluoromethyloxetanes via Transition Metal-Catalyzed Formal [2+2] Cycloaddition

This Lewis acid-promoted strategy was also used to synthesize unusual yet stable oxetene derivatives. Mikami and co-workers (284, 285) demonstrated that alkynylsilanes bearing electron-rich p-methoxyphenyl groups underwent the formal [2+2] cycloaddition to afford oxetenes with high ee when a chiral cationic BINAP–Pd complex was used (Scheme 69). Alkynes bearing aliphatic and aromatic groups gave the desired oxetanes in good to excellent yields and ee. (284) A variety of other conjugated alkynes were also compatible, including 1-naphthyl-, heteroaryl-, and vinyl-substituted alkynes. Remarkably, an ynamide was also able to undergo this transformation in excellent yield and ee, and the catalyst loading could be lowered to 0.5 mol %. These unusual oxetenes could undergo a variety of transformations, including reduction of the double bond with Pd/C and H₂ to give oxetane 198 (Scheme 70). (284)

Scheme 69. Synthesis of Chiral, Stable Oxetene Derivatives through Formal [2+2] Cycloaddition Mediated by a Chiral BINAP–Pd Complex

Scheme 70. Reduction of Trifluoromethylated Oxetene to the Corresponding Oxetane

5 Synthesis of Oxetane Derivatives from Oxetane-Containing Building Blocks

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Partly due to interest in the pharmaceutical industry, a number of oxetane building blocks have recently been developed and become increasingly available. In turn, this has furthered the exploration of oxetanes in drug discovery. An increasing selection of oxetane building blocks, largely 3-substituted examples, are now readily available from commercial suppliers (Figure 15). Certain examples, particularly modifications of oxetan-3-one, and 3-hydroxyoxetane are inexpensive, yet other simple substitution patterns remain very costly, for example, oxetane-3-carboxylic acid.

Figure 15. Some commercially available oxetane-containing building blocks.

Reactions of 3-hydroxyoxetane 199 were demonstrated by Baum et al. (286) in 1983 via the tosylate, formed by use of aqueous sodium hydroxide and tosyl chloride (Scheme 71). Reaction of 3-(tosyloxy)oxetane 200 with sodium azide yielded 3-azidooxetane 201 in 86% yield. Subsequent reaction with triphenylphosphine and then ammonolysis with liquid ammonia gave 3-aminooxetane 202 in excellent 96% yield. Oxidation to 3-nitrooxetane 203 was successful with m-CPBA. This could be then converted to the 3,3-dinitrooxetane by use of aqueous methanol and tetranitromethane. (286)

Scheme 71. Synthesis of 3-Amino- and 3-Nitrooxetane

Simple 3-bromo, iodo, and tosylate examples have been shown to be effective electrophiles for N-alkylation, especially on N-heteroaromatic compounds, with nucleophilic substitution occurring at the four-membered ring by an S_N2 mechanism. (287) Recent examples include applications in medicinal chemistry and in the preparation of substrates for ring-opening reactions (Scheme 72; (288, 289) also see section 3.1.3.1 for additional examples of similar reactions on more substituted substrates).

Scheme 72. S_N2 Reactions on Simple Oxetane Building Blocks^a

Nonetheless, outside the patent literature, there remain relatively few reactions on these simple substrates that maintain the oxetane ring. An example is oxidation of oxetane-3-methanol to the aldehyde, which has been achieved with Dess–Martin periodinane (290, 291) or PCC. (292) This section will give an overview of the transformations available on key oxetane building blocks and provide examples of their use in drug discovery efforts, including a survey of examples from the patent literature.

5.1 Carreira’s Oxetan-3-one

Oxetan-3-one was originally reported in 1973; (5, 287) however, studies from Carreira and co-workers (63, 65) since 2006 have developed this unit as an attractive electrophilic building block for the incorporation of oxetanes. There have been a large number of examples since, exploiting this ketone in reactions to incorporate an oxetane into a selection of important molecules.

In 1991, prior to Carreira’s studies, Kozikowski and Fauq (293) published a route to synthesize oxetane-containing amino acid derivatives as inhibitors for the glycine binding site of the N-methyl-d-aspartate (NMDA) receptor complex (Scheme 73). Oxetan-3-one was identified as a key intermediate and was synthesized in five steps from epichlorohydrin. A Strecker synthesis was then used to deliver the desired amino acid derivatives. Base hydrolysis of aminonitrileoxetane 204 at 95 °C for 2.5 h, followed by hydrogenolysis over Pd(OH)₂, delivered the amino acid 205 (Scheme 73). Alternatively, base hydrolysis at 50 °C for 30 min and then hydrogenolysis over Pd(OH)₂ resulted in the amino carboxamide.

Scheme 73. Synthesis of Two Oxetane Amino Acid Derivatives via Oxetan-3-one

Carreira and co-workers (63, 64) developed a general procedure for synthesis of 3-aryloxetan-3-ols from halogenated aromatic species, through a halogen–lithium exhange and then addition to oxetan-3-one (Scheme 74). This has been shown to be general for a large number of aromatic and hetereoaromatic groups, including but not limited to pyridine, pyrimidine, pyrazole, and ortho-, meta-, and para-substituted phenyl-containing examples. (289, 294-309) Similarly, alkynyl (289, 310-312) and vinyl (313, 314) organometallics have been added directly.

Scheme 74. Sample Synthesis of a 3-Aryloxetan-3-ol by Organometallic Addition

The 3-hydroxy group has provided a useful handle for further reactions, making 3-aryloxetan-3-ols interesting reactive intermediates. The earliest demonstration of replacement of a tertiary alcohol at the 3-position of an oxetane with a suitable nucleophile was in 2006 by Carreira and co-workers. (63) Fluorination by stoichiometric DAST was achieved in yields between 40% and 47% (Scheme 75). Subsequently, this methodology has been adopted and reported in numerous industrial medicinal chemistry patents for synthesis of 3-fluorooxetanes. (315-339) Fluorinating agents such as XtalFluor (325, 326) and Deoxo-Fluor (327-329) have also been found to be applicable for this transformation. The reaction has been shown to be tolerant of various preinstalled aryl substituents, with good yields (>70%) being reported for p-cyano-, (330-332)m-iodo-, (333) and p-bromophenyl (334, 335) and pyridyl (336-338) examples. Additionally, examples have been reported with pyrimidines, (329) pyrazoles, (339, 326) and more complex diaryls. (340-342) Chlorination of an oxetan-3-ol was also shown to be feasible; use of methanesulfonyl chloride and triethylamine at 55 °C formed the desired 3-chlorooxetane in 42% yield (Scheme 76). (64) This remains the only example of this transformation.

Scheme 75. Fluorination of Oxetan-3-ol by Use of Diethylaminosulfur Trifluoride

Scheme 76. Chlorination of 3-Phenyloxetan-3-ol by Use of Methanesulfonyl Chloride and Triethylamine

Acid-mediated dehydroxylation of 3-aryloxetan-3-ols has been successfully achieved by use of trifluoroacetic acid and triethylsilane as the hydride donor (Scheme 77a). (64) Although this reaction worked well for the p-anisyl derivative, neither the unsubstituted phenyl nor the 2,4-dimethylphenyl variants gave the desired product. A more general route was developed as a three-step, one-pot synthesis via the tosylate (Scheme 77b). (63) A low reaction temperature was required to prevent ring opening of the oxetane. (64)

Scheme 77. Dehydroxylation of Oxetan-3-ols

In 2013, scientists at Hoffman-La Roche (343) reported in a patent an example of a four-step synthesis of dehydroxylated oxetane 208 from oxetan-3-ol 206 (Scheme 77c). Near-quantitative conversion to the xanthate 207 was realized, with subsequent conversion to 3-aryloxetane 208 achieved in 38% yield by a Barton–McCombie deoxygenation with azobisisobutyronitrile (AIBN) and tributylstannane.

To generate 3-aminooxetanes, oxetan-3-one has been widely used in reductive amination sequences (also see section 5.3). (344-349) Hamzik and Brubaker (350) demonstrated the preparation of 3-aminooxetanes through condensation of oxetan-3-one and tert-butylsulfinimine (Bus), followed by addition of various organometallic reagents to imine 209 (Scheme 78a). Generation of an aziridine from the same imine with dimethyloxosulfonium methylide afforded aziridine 210 as an alternative electrophile. The activated aziridine opened preferentially, rather than the oxetane, generating 3-functionalized 3-aminooxetanes. The Bus group could be successfully removed with 4 N HCl in methanol in a short reaction time; longer reaction times gave ring opening with chloride. In a similar approach, Ellman and co-workers (351) described the Rh-catalyzed addition of aryl boroxines to the oxetane Bus-aldimines (Scheme 78b). The addition was tolerant of various functional groups on the aryl substituent, including phenol, ketone, and acetamide groups, though interestingly, omission of the phosphine ligand was required for a bromoaryl derivative to minimize side reactions.

Scheme 78. Preparation of 3-Aminooxetanes by Addition to an Imine^a

Brady and Carreira (352) reported the synthesis of 3-aminooxetanes by nucleophilic addition to N,O-acetals derived from oxetan-3-one. Alkynyl, vinyl, allyl, and allenyl trifluoroborates were added effectively by use of BF₃·OEt₂ to open the aminal, with tetrabutylammonium bromide included to solubilize the boron reagents (Scheme 79).

Scheme 79. Nucleophilic Addition of Carbon Nucleophiles onto Spirocyclic Oxetanes

In the initial studies of Carreira and co-workers, (63) oxetan-3-one was used to prepare a series of oxetane Michael acceptors, which have proven to be valuable building blocks in their own right. The synthesis of α,β-unsaturated ester 211 and aldehyde 212 was achieved by a Wittig reaction with the corresponding stabilized ylide reagents (Scheme 80). (63) Additionally, nitroalkene 213 was synthesized by condensation with nitromethane.

Scheme 80. Synthesis of Oxetane Michael Acceptors

These unsaturated units 211–213 underwent conjugate addition with various nucleophiles including amines, organocuprates, arylboronic acids, and vinylboronic acids, allowing the preparation of various 3,3-disubstituted oxetanes (Scheme 81). (63) The physicochemical properties of oxetane-containing compounds 2–6 were compared to examine the influence of the oxetane motif (see section 2). Carreira and co-workers (65) also prepared the comparable α,β-unsaturated sulfonyl, nitrile, and phosphonate oxetane derivatives. Vinyl sulfone derivative 214 enabled the preparation of 3-functionalized 3-methyloxetane derivatives through reductive removal of the sulfonyl group, for example, by the conjugate addition of amines, followed by treatment with Mg/MeOH (Scheme 82). Furthermore, conjugate addition reactions into acceptors, such as 211, followed by a small number of additional synthetic transformations, enabled the preparation of oxetane spirocycles (Scheme 83). (69, 2) In these examples, the oxetane was shown to be stable to a selection of organometallic reagents. An α-fluorinated derivative of 211 was prepared by Lequeux and co-workers (353) through a Julia–Kocienski reaction between oxetan-3-one and fluoromethylsulfones, which was used to prepared fluorine-containing 3,3-disubstituted oxetanes.

Scheme 81. Synthesis of 3,3-Diaryloxetanes via Conjugate Addition to Oxetane-Derived α,β-Unsaturated Ester, Aldehyde, and Nitroalkene

Scheme 82. Conjugate Addition to Vinyl Sulfone **214** and Reductive Removal

Scheme 83. Synthesis of Oxetane-Containing Spirocyclic Compounds Involving Conjugate Addition^a

Diederich and co-workers (354) showed that incorporation of a pendant oxetane improved the water solubility of 216, an inhibitor of the enzyme IspE (4-diphosphocytidyl-2C-methyl-d-erythritol kinase, EC 2.7.1.148), targeting the treatment of diseases such as malaria and tuberculosis (Scheme 84). The key step in synthesis of 216 was conjugate addition of 5-iodocytosine 215 to Michael acceptor 211, which gave 33% yield. Subsequent Sonogashira cross-coupling afforded 216 with a yield of 71%. Similarly, the synthesis of oxetanylthalidomide by Carreira and co-workers (80) (Table 2, section 2) involved conjugate addition of an amine to a nitroolefin derived from oxetanone.

Scheme 84. Oxetane-Containing IspE Inhibitor with Improved Aqueous Solubility

In 2014, Ellman and co-workers (355) reported catalytic enantioselective addition of thioacids to an oxetane-containing nitroalkene using bifunctional organocatalyst 217 (Scheme 85a). Michael addition into the oxetane-containing nitroalkene and subsequent enantioselective protonation led to the synthesis of 1,2-nitrothioacetate products in high yields and enantioselectivities for various substrates. Biomedically relevant 1,2-aminosulfonic acids were accessed via a high-yielding two-step route with complete retention of ee (Scheme 85b). Very recently, related work on conjugate addition, and subsequent enantioselective protonation, of pyrazol-5-ones to oxetane-containing trisubstituted nitroalkenes was reported. (356)

Scheme 85. Catalytic Enantioselective Synthesis of (a) 1,2-Nitrothioacetates and (b) 1,2-Aminosulfonic Acids

Carreira and co-workers (357) and Shipman and co-workers (358) simultaneously reported the use of oxetan-3-one to generate peptide mimics, with an aminooxetane providing a bioisostere for the amide linkage (Scheme 86). Peptides often confer poor properties as drug candidates because they are easily cleaved. Oxetanes may reduce the propensity for cleavage, providing an opportunity for new peptidomimetics with improved properties. In both cases, amine conjugate addition to nitroolefin 213 was used to introduce amino acid units. Shipman and co-workers (359) recently reported an adaptation of this approach to generate oxetane-containing diketopiperazine derivatives. Very recently, Jørgensen and co-workers (360) reported an organocatalyzed cycloaddition to oxetanyl nitroolefins to generate spirocyclohexene-oxetane scaffolds.

Scheme 86. Oxetane Peptidomimetics Formed via Conjugate Addition^a

Oxetan-3-one has been used in a number of complexity-generating reactions to incorporate oxetanes into interesting structural types. Shipman and co-workers (361) have used this unit in the Passerini reaction (Scheme 87a) and also in the Pictet–Spengler reaction (362) (Scheme 87b). Harrity and co-workers (363) applied their sydnone cycloadditions to an oxetane-containing motif in both intermolecular and intramolecular cycloadditions to form oxetane-containing pyrazole derivatives (Scheme 88).

Scheme 87. (a) Passerini and (b) Pictet–Spengler Reactions Involving Oxetan-3-one

Scheme 88. Inter- and Intramolecular Sydnone Cycloadditions

Bode and co-workers (364) have developed a powerful one-step protocol for synthesis of saturated N-heterocycles, using stannyl amine reagents in combination with aldehydes (SnAP protocol). This approach has been expanded to spirocyclic saturated N-heterocyclic examples, using ketones. (365) Significantly, oxetan-3-one was used in a key example to form an oxetane-containing spirocyclic piperazine (Scheme 89). Condensation of SnAP reagent 218 with oxetan-3-one generated an imine, which underwent Cu-catalyzed radical cyclization to form spirocyclic heterocycle 219.

Scheme 89. Synthesis of Spirocyclic Piperazine-Oxetane by Use of SnAP Reagents

In 2015, Soós and co-workers (366) showed that oxetan-3-one (as well as other four-membered cyclic ketones) would undergo selective direct cross-aldol reactions with other ketones, such as cyclopentanone, promoted by pyrrolidine (Scheme 90). The selectivity was attributed to the inherent angle strain of oxetan-3-one and relief of this strain during the conversion of C(sp²) to C(sp³). When unsymmetrical acyclic ketone butan-2-one was employed, l-proline was used as the organocatalyst at 80 °C to overcome the formation of a stable enamine adduct, but a mixture of regioisomers was obtained (1.5:1).

Scheme 90. Strain-Driven Direct Cross-Aldol Reaction with Oxetan-3-one

5.2 Cross-Coupling of Oxetane Building Blocks

Synthesis of aryloxetanes has been greatly expanded by the use of 3-iodooxetane in transition-metal cross-coupling reactions. In 2008, Duncton et al. (79) (Evotec) demonstrated the use of 3-iodooxetane in cross-coupling reactions with a series of arylboronic acids (Scheme 91). Under conditions developed by González-Bobes and Fu (367) for the cross-coupling of alkyl halides, a Ni-catalyzed Suzuki reaction achieved the coupling of 3-iodooxetane and also 3-iodoazetidines in moderate yields. The transformation was tolerant of various aryl groups but was unsuccessful with heterocyclic derivatives.

Scheme 91. Ni-Catalyzed Suzuki Coupling of 3-Iodooxetane^a

Zhang and Yang, (368) in 2015, developed a milder Ni-catalyzed Suzuki cross-coupling reaction of alkyl halides and arylboronic acids, using K₂CO₃ as the base instead of the more standard Li/KOtBu or Na/KHMDS. In the substrate scope, 3-iodooxetane was found to be a viable substrate, forming the aryloxetane product in 68% yield (Scheme 92).

Scheme 92. Ni-Catalyzed Suzuki Cross-Coupling Reaction of 3-Iodooxetane and Arylboronic Acids^a

To incorporate an oxetan-3-yl group into heteroaromatic bases, Duncton et al. (369) reported a Minisci reaction involving generation of the oxetane radical (Scheme 93). The reaction likely proceeded via addition of an oxetane radical to the protonated heterocycle, followed by rearomatization. Although the yields were generally low, the reaction proved tolerant of a number of different functional groups. Various N-heterocycles were successfully employed in the reaction, leading to synthetically useful yields, including quinoline, isoquinoline, pyridine, pyridazine, benzothiazole, benzimidiazole, quinoxaline, quinazoline, and phthalazine examples. Of particular note, due to the existing functionality present, were the hydroquinine and gefitinib derivatives 220 and 221.

Scheme 93. Fe-Catalyzed Synthesis of Heteroaryloxetanes from 3-Iodooxetane

Molander and co-workers (370) recently extended copper-catalyzed borylation methodology to prepare various heterocyclic trifluoroborates, several of which could be applied in a Minisci reaction with heteroaromatics. Several heterocyclic trifluoroborates were prepared from iodoheterocycles, including 3-iodooxetane (Scheme 94). The oxetane derivative was not demonstrated in the Minisci reaction; indeed, there are no reactions reported to date with oxetane boronates.

Scheme 94. Preparation of Oxetane Trifluoroborate

Molander et al. (371) established a Ni-catalyzed reductive coupling of saturated heterocyclic bromides with aryl and heteroaryl bromides. The reaction was developed by employing a high-throughput experimentation approach to screen Ni sources, ligands, additives, and solvents for the coupling of N-Boc-4-bromopiperidine with 4-bromoanisole. The scope of the saturated heterocycles included coupling of 3-bromooxetane with 4-bromoanisole in a yield of 43% (Scheme 95). Reaction conditions were reoptimized for heteroaromatic coupling partners, which had given poor yields under the previously developed conditions. Hence, the cross-coupling of N-Boc-5-bromoindole with 3-bromooxetane proceeded in 36% yield.

Scheme 95. Ni-Catalyzed Reductive Coupling of 3-Bromooxetane

Very recently, Buchwald and co-workers (372) reported a system for Lipshutz–Negishi cross-coupling under aqueous conditions, which included the coupling of 3-bromooxetane in high yields. A new ligand (VPhos) and Pd precatalyst were developed for coupling of alkyl bromides, particularly saturated heterocycles, and aromatic and heteroaromatic bromides and chlorides. Ley and co-workers (373) published two examples of 3-aryloxetanes synthesized in two steps from oxetan-3-one via a sulfonyl hydrazone intermediate 223 and subsequent metal-free coupling with boronic acids (Scheme 96). The reaction was optimized on N-Boc-piperidinone-derived tosyl hydrazine with 4-chlorophenylboronic acid. Replacement of the tosyl group of the hydrazone with a p-methoxyphenyl sulfonyl group, by use of 222, improved the observed yields.

Scheme 96. Metal-Free Coupling of Boronic Acids with Saturated Heterocycles by Use of Sulfonyl Hydrazones

Harrity and co-workers (374) prepared oxetane sulfinate salt 225 from 3-iodooxetane in a high-yielding three-step process (Scheme 97). Interestingly the sulfonate salt could be displaced from the pyridylsulfone 224 with a thiolate nucleophile in preference to oxetane ring opening. The sulfinate salts could be coupled with electron-rich indoles to introduce a sulfonyl group at the indole 3-position (226) by use of I₂ in MeOH.

Scheme 97. Preparation and Indole Coupling Reactions of Oxetane Sulfinate Salts

5.3 Applications in Medicinal Chemistry

The readily available oxetane units discussed above have recently found extensive use in medicinal chemistry. This section will cover the use of oxetanes in biologically active compounds prepared in drug discovery efforts. We will discuss examples where oxetanes have been used as part of an extensive screening and optimization approach. In most of these examples, the oxetane-containing example is the most bioactive compound and/or has the most desirable physicochemical properties as a potential therapeutic.

In 2011, Kinoshita et al. (346) reported the development of a highly potent and selective anaplastic lymphoma kinase (ALK) inhibitor as a promising therapeutic for cancer. The incorporation of an oxetane group, via reductive amination of oxetan-3-one, led to a significant improvement in the in vitro clearance level in mouse and human liver microsomes when compared to an isopropyl group at the same position (227, Figure 16). The N-oxetan-3-ylpiperidin-4-yl derivative had good metabolic stability and strong antitumor efficacy against KARPAS-299, a NPM-ALK-positive ALCL cell line. In an extension of this study, the introduction of an ethyl substituent on the phenyl ring (228) led to an almost 2-fold increase in potency against KARPAS-299, proposed to be a result of improved ALK selectivity over off-target kinases. (347)

Figure 16. Highly potent ALK inhibitors.

Stepan et al. (82, 83) explored arylsulfonamides as potential γ-secretase inhibitors toward treatment options for Alzheimer’s disease. Lead compound 229 contained a cyclohexyl substituent and displayed good potency but suffered from poor metabolic stability and solubility (Figure 17; also see section 2). Incorporation of an oxetane resulted in the greatest improvement in metabolic stability and lipophilicity. Overall, 2,4,4-trisubstituted analogue 231 was the most stable γ-secretase inhibitor of the series.

Figure 17. Comparison of metabolic stability of lead compound **229** compared to oxetane-containing analogues. CL_int,app (milliliters per minute per kilogram), shown in parentheses, is total intrinsic clearance obtained from scaling in vitro HLM half-lives.

Dowling et al. (81) at AstraZeneca described a series of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase (Figure 9, section 2). An N-oxetanyl group was used in place of a N-cyclopropyl group to reduce lipophilicity without the introduction of a basic group. Although the oxetane examples were potent CK2 inhibitors, they were 10-fold less active than cyclopropyl counterparts.

Scott et al. (375) at AstraZeneca developed a series of G-protein coupled receptor (GPCR) 119 agonists as a potential diabetes treatment. Initial development led to the discovery of a tert-butyl carbamate-containing compound that, although potent, suffered from nonideal aqueous solubility (24 μM). In order to improve this, a number of carbamates were examined. Replacing the tert-butyl group with a 3-substituted oxetane resulted in a dramatic increase in aqueous solubility to >2200 μM, over twice as soluble as the THF equivalent; however, these examples showed a reduction in potency. Addition of a methyl group to the oxetane increased the activity; ethyl and isopropyl groups did not further increase potency but led to an increase in metabolic instability. The alkyl substituent was revealed to be the site of metabolism, and to circumvent this, trifluoromethyloxetane-containing 233 was synthesized, which increased potency while maintaining a desirable solubility of 110 μM (Scheme 98). This was incorporated via pentafluorophenyl carbonate 232, developed specifically for this transformation after more standard approaches had failed.

Scheme 98. Preparation of Trifluoromethyl-Substituted Oxetane GPCR119 Agonist

Pei et al. (376) at Genentech developed a potent and selective oxetane-containing mammalian target of rapamycin (mTOR) inhibitor as a potential future cancer treatment. An advanced tetrahydroquinazoline lead molecule was further optimized to reduce the unfavorable time-dependent inhibition of cytochrome P450 (CYP). This was achieved by replacing an N-substituted pyrimidine 234 with an N-substituted oxetane 235, which prevented the interaction with CYPs via the pyrimidine unit (Figure 18). The oxetane unit, introduced by reductive amination of oxetan-3-one, reduced the basicity of the nitrogen atom compared to alkyl groups. It also led to lower hERG liability while maintaining the high potency of the initial advanced lead molecule. Following selection of the oxetane as the drug development candidate, further modification was carried out, replacing the tetrahydroquinazoline scaffold with a bicyclic pyrimidoaminotropane 236. (344) The oxetane unit was re-evaluated on this new backbone and compared to other substituents, and it was found to still possess the most desirable properties to be brought forward as a clinical candidate.

Figure 18. Potent and selective mTOR inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) is a gene related to Parkinson’s disease that has stimulated significant interest within neuroscience research. Estrada et al. (288) reported the development of highly potent, selective, and brain-penetrant small-molecule inhibitors of LRRK2 (Figure 19a). The lead compound was optimized to establish 237, with a pendent oxetane motif, as one of the best inhibitors, with an IC₅₀ value of 19 nM.

Figure 19. (a) Inhibitor of LRRK2. (b) Cathespin S inhibitor.

Jadhav et al. (377) at Lilly discovered a series of noncovalent inhibitors of cathespin S, useful as a potential treatment of abdominal aortic aneurysm. Following a medium-throughput screen, several hits were identified and one was selected for modification to improve its potency and physical properties. A key aspect of this modification process was replacing the N-methyl group on piperazine with an N-oxetanyl unit to modulate the basicity of the nitrogen atom and to lower the overall lipophilicity. This modification, along with others, led to the development of clinical candidate 238 (Figure 19b).

Zhang, Geng, and co-workers (348) developed 2,4-diarylaminopyrimidine analogues with a flexible amino acid side chain that are potent inhibitors against wild-type and mutant ALK kinases as a potential treatment against crizotinib-resistant non-small-cell lung cancer. Variation of the substitution of the primary amino group was studied, and it was found that use of a substituted piperazine, one of which contained pendant oxetane (239, Scheme 99), generated highly potent and selective ALK inhibitors. A primary amino acetamide proved to be more active (ALK IC₅₀ = 2.7 nM vs 4.9 nM for the oxetane) and this was chosen for further evaluation.

Scheme 99. 2,4-Diarylaminopyrimidine Analogues as Potent Inhibitors against Wild-Type and Mutant ALK Kinases

Phillips et al. (349) at Novartis developed GPCR TGR5 agonists, an attractive target for type 2 diabetes treatment and for chronic inflammation. An oxetane unit was used as part of a survey of alkyl substituents on a piperazine ring (240, Scheme 100). Although the oxetane unit successfully mitigated the issue of hERG risk and retained target potency, CYP3A4 inhibition and metabolic stability were not improved, so this example was not taken forward.

Scheme 100. GPCR TGR5 Agonists for Potential Type 2 Diabetes Treatment

Schoenfeld et al. (378) at Hoffmann-La Roche developed a series of hepatitis C virus inhibitors. An advanced lead structure was developed containing a tert-butyl group, which was succeptible to metabolic oxidation. An oxetane replacement showed similar activity. However, the increase in polarity led to reduced intrinsic permeability, so it was not advanced further (241, Figure 20a). The oxetane was synthesized via a C–O bond-forming step from the corresponding diol under Mitsonobu conditions.

Figure 20. (a) Oxetane-containing hepatitis C virus inhibitor. (b) 3-Sulfonyl oxetane inhibitor of MDM2.

Gonzalez et al. (379) (Amgen) utilized a 3-sulfonyl oxetane during variation of the N-alkyl substituent of a series of morpholinone inhibitors of the MDM2–p53 interaction. Disruption of MDM2 binding to p53 can reactivate the p53 pathway in tumor cells to allow cell cycle arrest and apoptosis. The 3-sulfonyl oxetane example 242 provided inhibitors with reduced cellular potency when compared to the more effective tert-butyl sulfone derivative (Figure 20b).

A novel class of γ-secretase modulators was developed by Austin et al. (380) at Satori Pharmaceuticals as a potential treatment of Alzheimer’s disease. An initial hit was identified from an extract of black cohosh root and developed to improve metabolic stability. A range of esters and carbamates was synthesized as bioisosteres to replace a glycoside moiety in order to improve chemical stability and decrease the topological polar surface area (tPSA) and HBD count. Oxetane examples were studied but did not prove to be potent inhibitors (243, Figure 21). Ultimately, increased activity correlated with increased basicity and hence nitrogen-containing groups, including azetidines, proved most potent. During an earlier structure–activity relationship study, (381) N-oxetanyl-substituted morpholine derivatives were utilized to examine the effects of varying other key parts of the structure.

Figure 21. γ-Secretase modulators with improved metabolic stability.

Procopiou et al. (382) at GlaxoSmithKline reported the development of a series of indazole arylsulfonamides as CC chemokine receptor 4 (CCR4) antagonists. A modified ligand lipophilicity index (LLE_AT), which combined lipophilicity, potency, and size and made comparisons to conventional ligand efficiency, was used as a metric to compare analogues. Oxetane amides 244 and 245 had inferior LLE_AT values compared to an acetamide group (Figure 22). The solubility increased for 244 and for THF and THP analogues but 245 was similar to the acetamide, attributed to the greater exposure of the oxygen in 244.

Figure 22. Oxetane-containing indazole CCR4 antagonists.

Dineen et al. (383) (Amgen) identified a potent inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE1). Previously reported aminooxazoline xanthene scaffold 246 was modified to improve BACE1 potency and prevent off-targert hERG channel activity. Principally this was achieved by incorporating a N atom in the 4-position of the xanthene core and by replacing the 5-pyrimidyl group with a 2-fluoro-3-pyridyl analogue (Figure 23). To further reduce hERG activity, the side chain at the 4-position was modified. An alkynyl side chain with a pendant methoxy group proved effective, maintaining BACE1 potency while reducing hERG binding affinity (247, Figure 23). However, oxidative demethylation of the methoxy group resulted in poor metabolic stability. An oxetane group was successfully incorporated to reduce this oxidative dealkylation, resulting in a compound with good stability in human and rat liver microsomes (248, Figure 23). Additionally, the oxetane unit was found to be stable in the presence of glutathione.

Figure 23. 4-Azaxanthene BACE1 inhibitors containing a pendent oxetane.

Plancher and co-workers (384) at Hoffmann-La Roche developed a series of 5-hydroxyindole-based histamine 3 receptor inverse agonists as a potential treatment for obesity. A 3-oxetanyl unit was assessed during modification of the basic piperidine side chain (249, Figure 24a). The oxetane led to the largest reduction in basicity with a pK_a of 6.4, compared with 9.7 for isopropyl, 9.1 for cyclobutyl, and 7.7 for cyclopropyl. The oxetane-containing example retained potent hH₃R binding (K_i = 23 nM), although it suffered from poor microsomal clearance.

Figure 24. (a) Oxetane modulating the basicity of H₃R agonists. (b) HIV-1 protease inhibitor. (c) Brain-penetrant 3-methoxy-substituted oxetane PI3K inhibitor. (d) Potent and selective DLK kinase inhibitor.

Samuelsson and co-workers (385) described a series of HIV-1 protease inhibitors with a number of different substituents containing hydrogen-bond acceptors. The isopropyl group from the l-Val methyl side chain, reported previously, (386) was replaced with a 3-oxetane (250), an ethoxymethyl, and a 1-methyl-substituted ethoxymethyl in order to “extend” a H-bond acceptor from the original position of the isopropyl (Figure 24b). This was designed to promote a positive interaction with the nitrogen of the Asp-30 residue of the HIV-1 protease backbone. Although the oxetane increased the tPSA and led to a significant lowering of logP, there was a considerable loss of potency compared to the original isopropyl group. The structural rigidity of the oxetane was proposed to be the cause of the loss in potency, forcing the oxygen atom to point away from the N–H of Asp-30 residue.

Heffron et al. (387) at Genentech undertook an in silico design approach in the development of inhibitors of phosphatidylinositol 3-kinase (PI3K), a target for potential cancer treatment, in particular, glioblastoma multiforme (GBM) brain tumors. Previous PI3K inhibitors discovered by Genentech suffered from poor penetration of the blood–brain barrier (BBB) due to high efflux. In order to improve the physicochemical properties of these inhibitors to increase BBB penetration, a central nervous system multiparameter optimization (CNS MPO) was utilized. In silico correlation of the CNS MPO score with desirable efflux ratios, and subsequently with the probability of metabolic stability, resulted in a very narrow range of physicochemical properties. Thus, a small number of molecules were selected for synthesis, including a number of oxetane-containing examples. One of the two key candidates discovered, a 3-methoxy-substituted oxetane (251, Figure 24c), was subjected to testing in mice; it successfully inhibited tumor growth beyond the BBB and was taken forward for further study toward clinical application.

Lewcock, Siu, and co-workers (388) have recently developed a series of inhibitors of dual leucine zipper kinase (DLK, MAP3K12), prominent in the regulation of neuronal degradation. Following the discovery of an initial hit through high-throughput screening, optimization led to oxetane 252 as a potent and selective DLK inhibitor (Figure 24d). A key aspect of the optimization was to reduce the lipophilicity and basicity of the analogues. An oxetane was successfully used to reduce the basicity of a key piperidine to limit efflux, important for a brain penetrant, while maintaining good metabolic stability. The bioactivity of this compound was shown in a number of animal models of neurodegenerative diseases.

5.4 Survey of Oxetanes in Drug Discovery Patents

The use of oxetanes disclosed in the patent literature has increased dramatically in the last 5 years. In this section, we examine the synthesis of oxetane-containing compounds that appeared in international or U.S. patents for use in medicinal chemistry or drug discovery programs. Here, oxetane-containing molecules from these patents are collated to include structure, source of the oxetane building block used, and bioactivity including any available data, along with the patent number and company (Table 18). In the cases where there are multiple examples of oxetanes in a given patent, an example has been selected, usually the most bioactive compound in the target screen if the data were available.

Table 18. Oxetanes Prepared in Patents during Drug Discovery Research

^{Table a}

See refs 391, 392, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, and 441.

One particular patent warrants further discussion. The original patent, filed by Hoffmann-La Roche, described the preparation of benzothiazepines and analogues for the treatment of respiratory syncytial viral (RSV) infection. (389) In this patent, the authors describe the synthesis of a large number of oxetane-containing compounds, several of which are reported to have very low IC₅₀ values in comparison to other non-oxetane-containing examples. This new class of RSV inhibitors displayed EC₅₀ values as low as 0.2 nM. Compound 255 (Scheme 101) was shown to have a less potent EC₅₀ value of 5 nM. Despite this, a recently disclosed patent describes the scale-up process for the synthesis of >5 kg of this compound. (390) The scale-up route begins with oxidation of [3-(bromomethyl)oxetan-3-yl]methanol 253 to the corresponding carboxylic acid, followed by carbamate formation and amination to form 254. A double amination with 2,4-dichloroquinazoline was then carried out, first with the primary aminooxetane fragment at the 4-position, followed by the benzothiazepine. Deprotection of the carbamate under acid conditions furnished 5.82 kg of 255 (Scheme 101).

Scheme 101. Large-Scale Preparation of Benzothiazepine RSV Inhibitors

6 Functionalization of Intact Oxetane Derivatives through Metalated and Radical Intermediates

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Recently a small number of examples of the functionalization of intact oxetane rings at the 2-position have emerged, involving deprotonation of oxetane derivatives. Capriati and co-workers (442) reported the synthesis of 2-substituted phenyloxetanes by formation of 2-lithio-2-phenyloxetane 256, which was chemically stable at −78 °C for up to 30 min (Scheme 102a). 2-Phenyloxetane was regioselectively deprotonated by use of sBuLi at −78 °C in THF and then trapped with reactive electrophiles, including alkyl halides as well as aromatic and aliphatic aldehydes and ketones, in good to excellent yields. Employing enantiomerically enriched 2-phenyloxetane resulted in racemic 2-substituted 2-phenyloxetanes in both polar (THF) and nonpolar (hexane/TMEDA) solvents, the lithiated intermediate being configurationally unstable. Reaction of the lithiated intermediate with cyclopropylmethyl bromide gave the butenyl-coupled product 257, which was cited as support for a single-electron transfer mechanism, also being the cause of racemization (Scheme 102b).

Scheme 102. Formation and Reactivity of 2-Lithio-2-phenyloxetane

Bull and co-workers (246) reported the regioselective lithiation of 2-tolylsulfonyl oxetane, followed by reaction with electrophiles to generate 2-substituted 2-sulfonyl oxetanes 258 (Scheme 103). Depending on the nature of the electrophile, nBuLi or LiHMDS could be employed as the base, in THF at −78 °C. These reaction conditions were developed to minimize a concurrent ortho-lithiation of the aromatic ring, directed by the sulfone moiety, that was particularly prominent when sBuLi was employed.

Scheme 103. Functionalization of 2-Arylsulfonyl Oxetanes via Lithation of the Oxetane Ring

Shipman and co-workers (443) reported the enantioselective synthesis of 2-substituted oxetan-3-ones by α-lithiation and alkylation of the (S/R)-1-amino-2-methoxymethylpyrrolidine (SAMP/RAMP) hydrazones 259 derived from oxetan-3-one (444) (Table 19). Deprotonation of hydrazone 259 with tBuLi to form the azaenolate, followed by electrophilic trapping, accessed 2-alkylated oxetanes 260 in good yields and diastereoselectivities. By use of ozone or oxalic acid, the alkylated hydrazones 260 were converted to the corresponding enantioenriched oxetan-3-ones 261 with ee values of up to 84%. Synthesis of a 2,2-disubstituted oxetan-3-one was achieved in 90% ee by a one-pot sequential metalation/alkylation protocol. Furthermore, 2,4-disubstituted examples could be accessed by thermal isomerization of the hydrazone configuration. Notably, there are no examples of the direct deprotonation of oxetane itself to form 2-metalated oxetane.

Table 19. Enantioselective Synthesis of 2-Substituted Oxetan-3-ones

entry	electrophile (RX)	yield 260 (%)	yield 261 (%)	ee (%)
1	BnBr	73	79	74
2	BrCH₂CH═CHPh	57	77	84
3	CH₃(CH₂)₇I	60	85	83
4	ICH₂CH₂CH₂OTBS	68	60	84
5	PhCHO	62	92^a	54, 2^b

1:1 dr.

(S,R) = 54; (S,S) = 2.

Oxetanes have recently been shown to be powerful directing groups for ortho-lithiation on aromatic rings. Capriati and co-workers (445) first developed this feature of the oxetane ring in 2012, using 2-methyl-2-phenyloxetane 262, without a benzylic proton, for regioselective synthesis of functionalized 2-aryloxetanes (Scheme 104). Treatment of oxetane 262 with sBuLi in Et₂O resulted in lithiation of the ortho position of the aryl ring, which was reacted with a variety of electrophiles including aldehydes, ketones, Me₃SiCl, and Bu₃SnCl in good yields. Alternatively, biaryl compounds could be accessed in one pot with a Li–B exchange followed by Suzuki cross-coupling with aryl and heteroaryl bromides. The oxetane substituent was shown to be as powerful a directing group as the dimethylaminomethyl group but not as effective as a sulfonyl group. (445) This allowed functional groups known to be weak directing groups to be present on the aromatic ring without affecting the regioselectivity of the metalation.

Scheme 104. Exploiting Ortho-Directing Ability of the Oxetane Ring To Access Functionalized 2-Aryloxetanes

Rouquet et al. (446) reported the regioselective ortho-functionalization of 3-oxetanylpyridines. Treating 3-(2-methyloxetan-2-yl)pyridine 263 with 1.4 equiv of nBuLi in the presence of TMEDA at −78 °C in Et₂O resulted in lithation at the pyridine C4 position (Scheme 105). A wide range of electrophiles was employed to generate the 4-functionalized pyridines, including, for example, diphenyl disulfide. The reaction was carried out on a gram scale, with methyl tert-butyl ether as the solvent and I₂ as the electrophile, to afford the 4-iodopyridine derivative in 67%.

Scheme 105. Ortho-Metalation on Pyridine Directed by an Oxetane

There have been two recent reports of radical functionalization at the 2-position of oxetane itself, maintaining the ring intact. (447-449) Ravelli et al. (447) reported the functionalization of oxetane through C–H activation by decatungstate photocatalyst TBADT, [(n-Bu)₄N]₄[W₁₀O₃₂], and addition to an electron-poor olefin (Table 20). Oxetane (3 equiv relative to the olefin) was irradiated in the presence of TBADT (2 mol %) in acetonitrile to generate the oxetane α-oxy radical. Substituted oxetanes were generated by use of terminal olefins and those with β-substituents. Employing olefins with two electron-withdrawing substituents resulted in good yields despite the increased steric hindrance. 3,3-Dimethyloxetane was also successfully employed in the reaction to form 2,3,3-trisubstituted derivatives. (447)

Table 20. Photocatalytic Synthesis of Oxetane Derivatives

When a 2-substituted oxetane was used, in the presence of a nonhindered olefin, a mixture of 2,2- and 2,4-disubstituted regioisomers was formed. When a bulky substituent (e.g., tBu) was present at C2 of the oxetane, reaction at the secondary radical was preferred (Scheme 106a). This was suggested to be due to a decreased reaction rate allowing back-hydrogen transfer to occur. Functionalization at the 3-position could be achieved by employing oxetanecarbaldehyde 264 (Scheme 106b). (447)

Scheme 106. Regioselectivity of Alkylation of Oxetane by Use of Decatungstate Photocatalyst

Jin and MacMillan (448) recently developed a visible-light-promoted photoredox catalytic method for direct α-arylation of dialkyl ethers with electron-deficient heteroarenes. Use of a highly tuned Ir-based photocatalyst in the presence of a persulfate salt generated an α-oxyalkyl radical, which underwent Minisci-type coupling with heteroarenes in excellent yields (Scheme 107a). The scope of the dialkyl ether component included a number of THFs, 1,4-dioxane, and 1,3-dioxolane as well as acyclic dialkyl ethers, which were all coupled with isoquinoline (77–93% yields). Most significant, however, was the use of oxetane as a substrate. Under the standard reaction conditions, an oxetanyl radical was generated; however, it underwent a ring-opening polymerization reaction. Modification of the reaction conditions by using MeCN as the sole solvent under more dilute conditions (0.05 vs 0.1 M), along with addition of (nBu)₄NCl to solubilize the persulfate anion, led to successful coupling of oxetane and isoquinoline, albeit in a yield of 42% (Scheme 107b).

Scheme 107. Direct α-Arylation of Ethers by Photoredox Catalysis–Minisci Reaction Sequence

7 Synthesis and Reactivity of 2-Methyleneoxetanes

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7.1 Synthesis of 2-Methyleneoxetanes

2-Methyleneoxetanes, oxetanes that bear an exocyclic C═C double bond at the 2-position, have been known since the late 1960s. The first examples of 2-methyleneoxetanes were synthesized by the Paternò–Büchi reaction. In 1966, Arnold and Glick (450) showed that excited-state carbonyl derivatives could be added to allenes under a high-pressure mercury arc lamp. Low yields were obtained and the major product of these reactions tended to be the bis-spirocyclic oxetanes (1,6-dioxaspiro[3.3]heptanes). Around the same time, Hammond and co-workers (451, 452) extended the Paternò–Büchi reaction with allenes and carbonyl compounds to include xanthone and benzaldehyde (Scheme 108a). The yields of the product oxetanes were higher, presumably due to the oxetane derivatives being more stable, but bis-spirocyclic oxetanes were also isolated. The use of fluorenone also afforded 2-methyleneoxetane 265; however, this was always isolated with the isomeric ketone 266 formed as a result of a rearrangement aided by the similar excitation energy of fluorenone and 2-methyleneoxetane 265 (Scheme 108b). (451, 452)

Scheme 108. 2-Methyleneoxetanes from Xanthone, Benzaldehyde, and Fluorenone

In the 1970s, Hudrlik et al. (453, 454) prepared the parent 2-methyleneoxetane 270 through a retro-Diels–Alder reaction (Scheme 109). A lengthy synthesis commenced with a Diels–Alder reaction between anthracene and α-acetoxyacrylonitrile to afford 267, followed by several transformations to afford diol 268. The primary alcohol was activated with MsCl and the crude reaction material was cyclized under Williamson etherification conditions (KOtBu/tBuOH), affording spirocyclic oxetane 269. Pyrolysis of oxetane–anthracene adduct by heating at 330–350 °C gave a mixture of products including 2-methyleneoxetane 270 (10%) along with other products (271–274) and remaining starting material. (454)

Scheme 109. First Synthesis of 2-Methyleneoxetane **270**

Hudrlik and Mohtady (455) also demonstrated that 2-methyleneoxetanes could be synthesized through intramolecular O-alkylation of enolates (Scheme 110). Treatment of ketone 275 with KH afforded 2-benzylideneoxetane 276 through O-alkylation, along with cyclobutanone 277 from C-alkylation. Each of the compounds in this synthetic route was taken through crude, so the yields for final products are estimated. The gem-dimethyl group was essential to facilitate cyclization.

Scheme 110. Synthesis of 2-Methyleneoxetanes via Intramolecular O-Alkylation of Enolates

With no further investigations reported for over 20 years, in 1996 Dollinger and Howell (456) reported a new approach to 2-methyleneoxetanes through methylenation of β-lactones (Scheme 111). Good yields were achieved with the Petasis reagent to generate varied substituted methyleneoxetanes, whereas with the more Lewis acidic Tebbe reagent the product could not be isolated. Howell has used this method extensively for preparation of 2-methyleneoxetanes and in numerous studies on their reactivity (see section 7.2).

Scheme 111. Synthesis of 2-Methyleneoxetanes via Methylenation of β-Lactones

A 2-methyleneoxetane analogue of Orlistat (278), a pancreatic lipase inhibitor, was prepared in 20% yield by use of the Petasis reagent to react at the β-lactone (Scheme 112). (457-459) This analogue was then directly compared against Orlistat in an assay against porcine pancreatic lipase (PPL) with tributyrin as the substrate. (459, 460) Comparative IC₅₀ values showed that analogue 278 displayed activity against PPL, albeit lower than Orlistat (IC₅₀ = 1.7 mg·mL^–1 vs IC₅₀ = 0.4 mg·mL^–1), and preliminary kinetic studies suggested irreversible inhibition. Despite the lower activity of the methyleneoxetane analogue, this was a significant result, as the carbonyl group of Orlistat was believed to be integral to both interaction and reaction with pancreatic lipase.

Scheme 112. Synthesis of 2-Methyleneoxetane Analogue of Orlistat

In an alternative approach, Fang and Li (461) reported the synthesis of 2-methyleneoxetanes by Cu-catalyzed intramolecular O-vinylation. γ-Bromohomoallylic alcohols such as 279 were prepared through a Sn-mediated Barbier reaction. When 1,10-phenanthroline ligands were used with CuI for the Ullmann cyclization, good yields of the desired 2-methyleneoxetane 280 were observed (Scheme 113). Only alkyne 281 was observed in the absence of a ligand, formed by direct elimination of HBr.

Scheme 113. Synthesis of 2-Methyleneoxetanes through Cu-Catalyzed O-Vinylation

Primary, secondary, and tertiary alcohols were all good substrates under these cyclization conditions (Scheme 114), with the order of reactivity of secondary alcohols being aliphatic > allylic > benzylic. The configuration of a substituted C═C double bond was retained in the cyclization, but the presence of the additional substituent required higher temperatures. γ-Chlorohomoallylic alcohol analogues were unreactive under the reaction conditions. The reaction was successful for other ring sizes, and interestingly, competition experiments established that the 4-exo ring closure was preferred over ring closure to form five- or six-membered rings. This was proposed to be due to precoordination of the Cu catalyst to the alkoxide prior to oxidative addition, leading to the formation of a favorable five-membered ring structure containing Cu, following oxidative addition. Interestingly, the equivalent Pd-catalyzed reactions favor the 5-exo-ring closure. (461)

Scheme 114. Sample Scope of Cu-Catalyzed Intramolecular Ullman Coupling

In 2011, Saunders and Miller (462) showed that formal cycloadditions of allenoates and 2,2,2-trifluoroacetophenones could be achieved to form either dihydrofurans or 2-alkylideneoxetanes when Lewis basic catalysts were used. While phosphines catalyzed the [3+2] cycloaddition to give the dihydrofurans, 1,4-diazobicyclo[2.2.2]octane (DABCO) catalyzed the formal [2+2] cycloaddition to form 2-alkylideneoxetanes 282 (Scheme 115).

Scheme 115. Synthesis of 4-Trifluoromethyl-2-methyleneoxetanes via Lewis Base-Catalyzed Formal [2+2] Cycloaddition

The reaction was successful with various aryl substituents: 4-halo-substituted aromatics were well tolerated, but low yields were obtained with electron-rich aryl substituents. Ketones that did not possess a trifluoromethyl group were unreactive. Substitution at the γ-position of the allenic esters was also viable, with oxetane 283 formed in 51% yield (2.9:1 dr). The proposed mechanism involved addition of DABCO to the allenoate, followed by γ-addition to the ketone (Scheme 116). The subsequent oxyanion could undergo conjugate addition onto the β-carbon, re-forming the enolate, which then eliminated DABCO. Though the reaction progressed when catalytic amounts of DABCO were used, the optimized conditions used stoichiometric amounts to obtain higher yields.

Scheme 116. Proposed Mechanism for Lewis Base-Catalyzed Formal [2+2] Cycloaddition of Allenoates and 2,2,2-Trifluoroacetophenones

At around the same time, Ye and co-workers (463) reported a similar reaction that used catalytic quantities of DABCO (20 mol %) in THF at 0 °C to form 2-alkylideneoxetanes 284 (Table 21). Again, electron-rich ketones gave lower yields, and some sterically bulky ester groups (Cy and t-Bu) were tolerated on the allenoate.

Table 21. Selected Examples of 2-Alkylideneoxetanes Synthesized by Use of Catalytic Amounts of DABCO

entry	R	Ar	yield (%)
1	Et	3-MeC₆H₄	73
2	Et	2-thienyl	47
3	Cy	Ph	79
4	tBu	Ph	60

In 2012, an asymmetric version of this Lewis base-catalyzed formal [2+2] cycloaddition was reported (Scheme 117). (464) The optimized conditions used 20 mol % β-isocupreidine 285 as catalyst and 10 equiv of water as an additive in THF at −15 °C for 6 days. High yields and good to excellent ee were obtained with a variety of substrates including both electron-rich and electron-deficient aromatics. As well as trifluoromethylaryl ketones, the reaction worked similarly with a pentafluoroethyl ketone (286) and with a pentyltrifluoromethyl ketone (287). The proposed role of water was to stabilize the transition state for γ-addition of the extended enolate to the ketone through formation of a six-membered hydrogen-bonded ring with the hydroxy group of the catalyst.

Scheme 117. Asymmetric Formal [2+2] Cycloaddition with β-Isocupreidine **285** as Catalyst

A formal [2+2] cycloaddition was developed by Selig et al. (465) to form more substituted 2-alkylideneoxetanes through the incorporation of additional substituents on the allenoate. By use of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), a highly active nitrogen Lewis base, (466) for allenoate activation, a variety of γ-substituted allenoates were transformed into highly substituted 2-alkylideneoxetanes (Scheme 118). All four possible isomers were formed during the reaction, but increasing the steric bulk of the γ-substituent led to increased formation of the Z isomer. Electron-rich ketone substrates gave higher yields than electron-deficient ketones, due to the electron-deficient ketones undergoing addition reactions with TBD itself, poisoning the catalyst. An α,γ-disubstituted allenoate was also a viable substrate, forming a highly substituted oxetane in good yield and diastereoselectivity with a slightly higher catalyst loading (30 mol %) and a longer reaction time (288).

Scheme 118. Use of TBD as Lewis Base Catalyst for Synthesis of Highly Substituted 2-Alkylideneoxetanes

7.2 Reactivity of 2-Methyleneoxetanes

The reactivity of 2-methyleneoxetanes can be separated into two types: (i) ring opening of the oxetane and (ii) functionalization of the C═C double bond. Ring-opening reactions include conversion to homopropargylic alcohols through elimination, (467) nucleophilic attack with carbon or heteroatom nucleophiles at C4 to generate ketones, (468, 469) and reductive ring opening of 4-aryl derivatives by use of Li/4,4′-di-tert-butylbiphenyl (DTBB) to generate ketones. (470, 471) Certain 2-methyleneoxetanes have also been reported to undergo a conversion to α,β-unsaturated methyl ketones at high temperatures (Scheme 119). (472) The incorporation of a silyl group at the 3-position of the ring in 289 enhanced the reaction, which was proposed to occur by alkene isomerization through oxetene 291, followed by a 4π-electron electrocyclic ring opening to give ketone 290.

Scheme 119. Tandem Alkene Isomerization/Electrocyclic Ring Opening of 2-Methyleneoxetanes

The first example of functionalization of the exocyclic C═C double bond of a 2-methyleneoxetane, such as 292, was reported in 1998 through epoxidation to form 1,5-dioxaspiro[3.2]hexanes (e.g., 293, Scheme 120). (393) By use of anhydrous, acetone-free dimethyldioxirane (DMDO) to provide neutral conditions, (473) quantitative yields of the sensitive spirocycles were obtained from a variety of substituted 2-methyleneoxetane derivatives. Moderate diastereoselectivity was observed with one substituent at the C3 position, but an additional substituent at C3 or any substitution at the C4 position lowered the dr.

Scheme 120. Epoxidation of 2-Methyleneoxetanes: Synthesis of 1,5-Dioxaspiro[3.2]hexanes

The internal acetal of these spirocycles, such as 294, underwent hydrolysis in the absence of acid to afford ketones such as 295 in very high yields (Scheme 121a). (393) This reactivity was then reported for a variety of nucleophiles: oxygen nucleophiles gave good yields of hydroxy ketones, thiophenol was slow to react but the sodium thiolate gave a good yield, imidazole gave low yields, and ring opening followed by reduction to a 1,3-diol occurred with LiAlH₄ (Scheme 121b). (474) Unexpectedly, the use of DIBAL gave nucleophilic attack at the internal position of the epoxide to leave the oxetane ring intact (296). Coordination of the Lewis acid to the epoxide oxygen was proposed with participation of an oxetane oxonium ion. Ring opening of the epoxide, leaving the oxetane ring intact, also occurred with nucleophiles such as TMSN₃ (297) and AlMe₃ (298).

Scheme 121. Nucleophilic Ring Opening of 1,5-Dioxaspiro[3.2]hexanes

A detailed study of heteroaromatic nucleophiles was undertaken with the epoxide of 3-phenyl-2-methyleneoxetane 293 which related pK_a of the nucleophile to the reaction product. (475) Both imidazole and TMS-imidazole gave oxetane ring opening, pyrrole and indole did not react, and 1,2,4-triazole and its TMS-linked analogue also caused oxetane ring opening. However, 1,2,3-triazole gave the 2,2-disubstituted oxetane, as did benzotriazole, TMS-benzotriazole, and tetrazole. This study concluded that more acidic nucleophiles formed the 2,2-disubstituted oxetanes, potentially due to activation of the epoxide so that intramolecular oxonium formation could occur more easily. Howell and co-workers (475) therefore investigated other Lewis acids, and the addition of Mg(OTf)₂ with 1,2,4-triazole, which originally gave oxetane ring opening (299), gave 2,2-disubstituted oxetane formation (300, Scheme 122).

Scheme 122. Synthesis of 2,2-Disubstituted Oxetane **300** by Use of Mg(OTf)₂ and 1,2,4-Triazole

The tandem ring opening of 1,5-dioxaspiro[3.2]hexanes was utilized in synthesis of the challenging sphingoid base of glycosphingolipids. (476) 1,5-Dioxaspiro[3.2]hexane 301 was prepared in three steps from N-Boc-protected l-serine (Scheme 123). Addition of a higher-order cuprate led to formation of ketone 302 through nucleophilic attack at the least hindered epoxide carbon, which was converted to d-erythro-dihydrosphingosine 303 in two steps. 1,5-Dioxaspiro[3.2]hexane 301 also underwent facile epoxide ring opening with acetic acid, and subsequent functionalization converted ketone 304 to d-xylo-phytosphingosine 305 in six steps. A similar strategy was used in the synthesis of epi-oxetin, involving a DIBAL opening of epoxide 306 (Scheme 124). (477)

Scheme 123. Synthesis of d-*erythro*-Dihydrosphingosine and d-*xylo*-Phytosphingosine by Tandem Ring Opening of 1,5-Dioxaspiro[3.2]hexane

Scheme 124. Synthesis of *epi*-Oxetin through DIBAL Opening of 1,5-Dioxaspiro[3.2]hexane^a

In 2012, ring opening of spirocyclic epoxide 307 was used to generate hydroxymethyloxetane 308 as a possible intermediate in the synthesis of Laureatin. (478) However, treatment of derivative 309 with NBS instead mediated a rearrangement, forming epoxytetrahydrofuran 310 in a 51% yield (Scheme 125).

Scheme 125. Unexpected Rearrangement of Oxetane **309** Affording Epoxytetrahydrofuran

Howell and co-workers (479) also examined the reactivity of the enol ether of 2-methyleneoxetanes with haloelectrophiles, intending to trap the intermediate oxonium ion. Treatment of oxetane 311 with KOtBu, followed by the addition of I₂, gave the first example of a [2.2.0] fused ketal, 312, in 40% yield (Scheme 126).

Scheme 126. Synthesis of [2.2.0]-Fused Ketal

A similar strategy was used to access oxetane-containing psico-nucleosides, that is, with a hydroxymethyl group adjacent to the base, related to the natural product oxetanocin A. This was achieved through electrophilic addition of F⁺ followed by nucleophilic attack of the nucleobase (Scheme 127). (480) From 2-methyleneoxetane 313, selectfluor gave a good yield for nucleobase incorporation, but both N7 (314) and competing N9 alkylation (315) occurred. After multiple purifications, 314 was obtained as a 37:63 mixture (α:β epimers, 42% yield) and 315 as a 23:77 mixture (α:β epimers, 34% yield), with both favoring the desired β-isomers. Oxetane-containing psico-nucleosides 316 and 317 were then prepared through a substitution reaction with ammonia, followed by deprotection of the silyl ethers. (480)

Scheme 127. Synthesis of Oxetane-Containing *psico*-Nucleosides

Cyclopropanation of the exocyclic C═C double bond of 2-methyleneoxetanes was achieved to form 4-oxaspiro[2.3]hexanes (Scheme 128). (481) Using ZnEt₂ and CH₂CI₂ in the modification by Furukawa et al. (482) of the Simmons–Smith reaction gave a good yield of spirocyclic cyclopropanes, providing the reaction temperature was not raised above 0 °C, across a variety of substituted oxetanes. Bekolo and Howell (481) showed that 4-oxaspiro[2.3]hexanes underwent rearrangement when treated with BF₃·OEt₂ (Scheme 129). For example, treatment of oxetanes 318–320 with BF₃·Et₂O led to three different products being formed: cyclobutanone 321, THF 322, and cyclopentanone 323. The reaction was proposed to proceed via ring opening to form carbocationic intermediates, which could rearrange through cyclopropane opening and hydride shifts, with the pathway influenced by the substitution on the oxetane ring.

Scheme 128. Cyclopropanation of 2-Methyleneoxetanes To Form 2-Oxaspiro[2.3]hexanes

Scheme 129. Rearrangement of 4-Oxaspirohexanes Catalyzed by BF₃·Et₂O

Oxaspirohexanes that were synthesized from 2-methyleneoxetanes also underwent rearrangement catalyzed by Zeise’s Pt(II) dimer. (483) Monosubstituted as well as 5,6-trans-disubstituted oxaspirohexanes rearranged in good yields via a platinacyclobutane intermediate (Scheme 130). 5,6-cis-disubstituted oxaspirohexanes ring-opened to afford allyl chlorides as the major product.

Scheme 130. Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans via Platinacyclobutane Intermediate

8 Ring-Opening and Ring-Expansion Reactions of Oxetanes

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In an apparent contradication with the stability required of the oxetane ring in many medicinal chemistry applications, the strain present in the ring (106 kJ·mol^–1) renders oxetanes useful synthetic intermediates. (31, 32) This section considers reactions that result in ring opening of oxetanes, through attack at the 2-position releasing the ring strain, and also ring-expansion reactions that form larger heterocyclic systems. Here, ring expansion is defined as when the oxygen atom from the oxetane ring remains in the new ring structure formed in the relevant reaction; ring opening is the term used when the oxetane O-atom is not in the new ring, even if a ring is formed. Readers are also directed to recent reviews by Malapit and Howell, (7) on aspects of using oxetanes in the preparation of other heterocycles, and by Sun and co-workers, (8) on enantioselective oxetane ring-opening desymmetrization reactions. Ring-opening reactions of oxetanones are not covered specifically, (5) and for ring-opening reactions of 2-methyleneoxetanes, see section 7.

8.1 Ring-Opening Reactions of Oxetanes

Under acidic conditions, the oxetane ring can be opened with simple nucleophiles, including hydrolysis to give 1,3-glycols. (484, 485) Various nucleophiles have been employed, including amines, (486-489) KPPh₂, (490) lithiated alkynes, (491-493) TMSCN, (494, 495) allyl silanes, (496) LiAlH_4, (497) and azaenolates. (498) Lithium enolates have been used to open mono- or disubstituted oxetanes in the presence of BF₃·OEt₂. (499) Gassman and Haberman (495) reported the treatment of 2-substituted and 2,2-disubstituted oxetanes with TMSCN in the presence of zinc iodide to afford γ-hydroxyisonitriles 324 in yields of 73–94%, by ring opening at the more substituted position (Scheme 131). The isonitriles were converted into the corresponding γ-amino alcohols 325 in 65–81%, following deprotection and hydrolysis.

Scheme 131. Ring Opening of Oxetanes by Attack of an Isonitrile Nucleophile

Organometallic reagents alone can open oxetane at higher temperatures. In 1916, oxetane was treated with n-propylmagnesium bromide under reflux in ether/benzene, which resulted in the formation of n-hexanol in 49% yield. (500) This prompted the seminal work by Searles (501) on reaction of oxetane with organometallic compounds. Oxetane, with a variety of aromatic and aliphatic organometallic reagents, such as PhMgBr, BnMgCl, and PhLi, was heated under reflux in benzene for 4 h to afford the corresponding open-chain alcohols in moderate to good yields (Table 22). It is notable that ring opening occurred, whereas in the more strained epoxide, these organometallic reagents would be likely to result in deprotonation on the ring. (502, 503)

Table 22. Ring Opening of Oxetane with Organometallic Reagents

entry	Grignard reagent	yield (%)
1	PhMgBr	84
2	CyMgBr	28
3	1-naphthyl-MgBr	80
4	i-PrMgCl	28
5	BnMgCl	83
6	PhLi	85
7	n-BuLi	28

Huynh et al. (504) reported milder, room-temperature reaction conditions for the opening of oxetane by Grignard reagents in the presence of CuI (10 mol %) for 20 h. Grignard reagents, including nBuMgCl, PhMgBr, and allyl-MgBr, successfully reacted with oxetane with yields of 50–75%. High-temperature reactions have also been reported. (505)

In 2008, Pineschi and co-workers (506) developed a regioselective ring opening of 2-aryloxetanes with aryl borates under mild, neutral conditions. The use of enantiomerically pure 2-phenyloxetane led to the formation of enantioenriched β-aryloxy alcohols such as 327 or 328 with little reduction in ee. This was proposed to occur via intramolecular delivery of the aryloxy group in a six-membered transition state (329, Scheme 132), resulting in retention of configuration at the reacting center. When electron-rich aryl borates were used, the C-alkylation product dominated, formed via a Friedel–Crafts process, in low ee (326). A range of aryl borates could be used, including a number of ortho-halo-substituted examples and a catechol borate, in yields up to 86% and up to 86% ee (e.g., 328, Scheme 132).

Scheme 132. Ring Opening of 2-Aryloxetanes with Aryl Borates

In 2002, Dussault et al. (113) reported the regioselective Lewis acid-catalyzed ring opening of oxetanes to afford enantiomerically enriched 1,3-hydroperoxy alcohols and 1,3-peroxy alcohols which could be converted into enantiomerically enriched 1,2,4-trioxepanes. Enantioenriched oxetanes were treated with ethereal H₂O₂ in the presence of Lewis acids to form hydroperoxy alcohols. No reaction was observed when MgCl₂, ZnCl₂, or BF₃·OEt₂ was employed, and the use of TFA, CSA, BF₃·OEt₂, or H₂SO₄ resulted in significant amounts of 1,3-diol being formed. However, treating the oxetanes with ethereal H₂O₂ in the presence of TMSOTf, Yb(OTf)₃, or Sc(OTf)₃ resulted in the desired products 330 being formed in good yields (Table 23). The reaction was extended to tertiary oxetanes with alkyl hydroperoxides, such as t-BuOOH, cumyl-OOH, and THP-OOH, to produce 3-peroxy alkanols in yields of 39–51%.

Table 23. Opening of Substituted Oxetanes with Hydrogen Peroxide To Access Hydroperoxy Alcohols

Dai and Dussault (507) reported the corresponding intramolecular reaction in 2005. Oxetanes 331 were treated with O₃ in methanol to give intermediate 332, which underwent a 5-exo cyclization to afford 1,2-dioxolanes 333 as a 1:1 mixture of cis and trans isomers (Table 24). Interestingly, cyclization onto a monosubstituted oxetane gave the desired product despite the corresponding intermolecular reaction being unsuccessful. Alkyl hydroperoxides were also generated by cobalt-mediated reductive dioxygenation, such as from 334, which afforded triethylsilyl peroxide 335 in 80% yield (Scheme 133). Deprotection with HF followed by 5-exo cyclization afforded 1,2-dioxolane 336. (507)

Table 24. Intramolecular Opening of Substituted Oxetanes

entry	R	R¹	R²	yield (%)
1	Me	Me	H	57
2	C₆H₁₃	Me	H	73
3	C₆H₁₃	H	H	77
4	C₆H₁₃	Me	Me	72

Scheme 133. Intramolecular Opening of Substituted Oxetanes with Alkyl Hydroperoxides

Han and Wu (508) reported the perhydrolysis of tertiary and secondary oxetanes in the presence of a molybdenum species, Na₂MoO₄-Gly, in H₂O₂/t-BuOMe. In addition to the desired product 337, alcohol 338 (often not isolated) and elimination product 339 were formed (Table 25). Different diastereoisomers showed differences in the stereoselectivity of the reaction (Table 25, entries 3 and 4). Secondary oxetanes were less reactive than tertiary oxetanes under the reaction conditions; therefore a more acidic catalyst, PMA (phosphomolybdic acid), was required. (508)

Table 25. Perhydrolysis of Oxetanes in the Presence of Molybdenum Species

In 2014, Okamoto and co-workers (509) reported the ring opening of 2-substituted oxetanes by Fe-catalyzed reductive magnesiation at the 2-position to afford substituted 3-oxidopropylmagnesium compounds such as 340 in excellent yields. 2-Phenyloxetane was treated with a Grignard reagent in THF in the presence of FeCl₃ to form the ring-opened product 341 in 54% yield after workup, and this yield was increased to 99% by addition of a phosphine ligand (Scheme 134). Ring opening occurred in high yields under modified conditions when 2-alkyl, 2,2-diphenyloxetane, and 2,2-phenylmethyloxetane substrates were used, but no reaction occurred when a 3,3-disubstituted oxetane was investigated.

Scheme 134. Fe-Catalyzed Reductive Magnesiation of 2-Phenyloxetane

The 3-oxidopropylmagnesium intermediates 342 were also successfully quenched with electrophiles (Table 26). Okamoto and co-workers (509) proposed that the reaction proceeded via a radical mechanism, involving a low-valent Fe species. This proposal was supported by the loss of stereochemical information when diastereomeric pairs of oxetanes were used.

Table 26. Electrophilic Trapping of Oxidopropylmagnesium Compounds

In 2013, Okamoto and co-workers (510) reported the reductive ring-opening reaction of oxetanes catalyzed by a low-valent titanium species, formed from a titanatrane complex (Scheme 135). Complex 344 was treated with Me₃SiCl and Mg powder to form a low-valent titanium alkoxide that, in the presence of 1,4-cyclohexadiene, reduced oxetanes to alcohols in good yields. 3,3-Disubstituted oxetanes, 2-monoaryl and 2-monoalkyl oxetanes, 2,2-disubstituted oxetanes, and spiro compounds were all successfully reduced to the corresponding alcohols (Table 27). Okamoto and co-workers (510) proposed that the oxetane coordinated to an intermediate Ti complex and then underwent a single-electron transfer to generate a titanoxy radical. This resulting radical could then abstract hydrogen from 1,4-cyclohexadiene. The stability of this radical intermediate affected the regioselectivity of the reaction, generally resulting in formation of the less-substituted alcohols as the major products.

Scheme 135. Formation of Primary Alcohols by Ring Opening of Oxetanes

Table 27. Radical Ring Opening of Oxetanes by Treatment with Low-Valent Titanium Complex 344

Murakami and co-workers, (511) in 2013, showed that cyclobutanols underwent ring opening and addition to isocyanates with a Rh catalyst. Conventionally, carbamates would be formed when cyclobutanols are reacted with isocyanates, but this combination of Rh catalyst and 1,1′-bis(diphenylphosphino)ferrocene (DPPF) ligand directed isocyanate addition through the C-atom, generating amide derivatives. As part of the substrate scope, it was shown that oxetanols were compatible with this Rh-catalyzed C-carbamoylation (Scheme 136). The Rh-catalyzed C-carbamoylation of oxetanols occurred in very good yields, and the stereochemical integrity of an enantioenriched oxetanol (>98% ee; >20:1 dr) was retained in ring-opened amide (>98% ee).

Scheme 136. Rh-Catalyzed C-Carbamoylation of Oxetanols and Isocyanates

8.1.1 Intramolecular Ring Opening

The use of intramolecular nucleophiles can be effective in generating new ring systems. In the total synthesis of (±)-gelsemine, Danishefsky and co-workers (512, 513) utilized a Lewis acid-mediated intramolecular oxetane ring-opening strategy with a nitrogen nucleophile (Scheme 137).

Scheme 137. Oxetane Ring Opening in Total Synthesis of (±)-Gelsemine^a

In 1996, Bach and Kather (514) reported intramolecular ring-opening reactions of oxetanes 345 to give diastereomerically pure sulfur, nitrogen, and oxygen heterocycles 346 (Table 28). A Paternò–Büchi reaction of silyl enol ethers followed by a Mitsunobu reaction generated oxygen-, sulfur-, or nitrogen-containing precursors. (514, 515) Cyclization to six- and seven-membered heterocycles was achieved by treatment with organometallic reagents and heating. A tetrahydropyran was synthesized in 54% yield by removing a pivaloyl protecting group with MeLi in DME and then heating at reflux to promote cyclization (Table 28, entry 1). However, the seven-membered oxepane derivative could not be generated under the same conditions, with only deprotection being observed (entry 2). Replacing dimethoxyethane (DME) with high-boiling (162 °C) diglyme allowed the oxepane derivative to be synthesized in a 32% yield as a mixture of diastereomers. (515) Thiotetrahydropyran and thiooxepane derivatives could be delivered as single diastereoisomers by use of MeLi and MeMgBr, respectively (entries 3 and 4). Similarly, use of MeMgBr yielded the piperidine derivative in a synthetically useful 52% yield (entry 5). The Mg cation was thought to coordinate to the oxetane oxygen, encouraging nucleophilic substitution.

Table 28. Scope of Ring-Opening Reaction^a

entry	n	X	PG	reagent	time (h)	yield (%)
1	1	O	Piv	MeLi	6	54
2	2	O	Piv	MeLi	5	0
3	1	S	Ac	MeLi	4	91
4	2	S	Ac	MeMgBr	5	54
5	1	NTs	H	MeMgBr	5	52

Bach and Kather. (514)

Similarly, oxetane 347, prepared in three steps from 2-hydroxyacetophenone by Paternò–Büchi reaction, could be cyclized by use of MeLi to give a mixture of dihydrobenzofuran derivatives 348 and 349, with the diol as the major product and the monosilylated derivative as the minor product (Scheme 138). (514, 515) Treatment with MeMgBr gave the benzofuran derivative 350, where the silyl ether was eliminated.

Scheme 138. Intramolecular Cyclization to Dihydrobenzofuran or Benzofuran Derivatives

Grainger and co-workers (516) examined the ring opening of oxetanes to yield dihydrobenzofurans. A Paternò–Büchi reaction formed the oxetane moiety, and then acid-promoted intramolecular cyclization occurred with a proximal arylmethoxy group acting as the nucleophile (Scheme 139). The use of 10 equiv of HCl gave the bis-spirocyclic hydroxy products in yields between 34% and 78%. Acetyl chloride could also be used as a promoter to give acetate derivatives.

Scheme 139. Synthesis of Bis-Spirocycles through Paternò–Büchi Reaction and Acid-Promoted Intramolecular Cyclization

In 2012, Sun and co-workers (517) reported the synthesis of eight-membered lactones via a [6 + 2] cyclization process between oxetane-containing benzaldehydes and ynol silyl ethers. When oxetane 351 was treated with siloxy alkynes 352 in the presence of trifluoromethanesulfonimide as a Lewis acid, eight-membered lactones 353 were formed (Table 29). Nucleophilic attack on the aldehyde moiety of oxetane 351 resulted in an intramolecular oxetane ring-opening process. Oxetanes with aryl linkers substituted with an electron-withdrawing or electron-donating group could be employed in the reaction. Interestingly, when the oxetane ring was substituted by an epoxide, a similar intermolecular reaction was not observed. Instead an intermolecular homocyclization between the oxirane and the aldehyde moiety occurred.

Table 29. Intramolecular Ring Opening of Oxetane Resulting in Formation of Eight-Membered Lactones

Yadav et al. (518) utilized an acid-catalyzed oxetane ring-opening approach to form a key substituted tetrahydropyran (THP) skeleton in synthesis of the C1–C17 fragment of the polyether natural product salinomycin. By use of a model substrate, the desired regioselective ring opening was achieved with both Lewis and Brønsted acids with MeOH as the solvent; however, the methyl ether product was favored over THP. Switching to an aprotic solvent (CH₂Cl₂) led to selective formation of the THP, and the use of a 15:1 ratio of CH₂Cl₂:iPrOH resulted in significantly faster reaction times with either camphorsulfonic acid or p-toluenesulfonic acid (entry 1, Table 30). The reaction was viable for formation of a number of more complex THPs, particularly those with multiple substituents (entries 2 and 3). Formation of the key THP ring for the C1–C17 fragment of salinomycin proceeded cleanly in 92% yield (entry 4). The C1–C11 fragment of (+)-zincophorin was formed from the corresponding oxetane in 83% yield in a similar manner (entry 5). Subsequent protecting-group manipulation allowed access to the desired fragment. (519)

Table 30. Acid-Catalyzed Tetrahydropyran Formation by Intramolecular Oxetane Ring Opening: Natural Product Fragments^a

^{Table a}

Conditions: CSA (1 equiv), CH₂Cl₂/iPrOH (15:1), 0 °C to rt, 2–2.5 h. ^bReaction was run for 48 h. ^cReaction was run overnight.

In 2015, Britton and co-workers (520, 521) reported a total synthesis of the marine fungus-derived natural product ascospiroketal, targeted due to potential biological activity. An Ag(I)-promoted oxetane ring opening was used to install the desired tricyclic structure. A brief screen of Ag(I) salts found a combination of AgBF₄ and Ag₂O gave the best yield of 82% with complete diastereoselectivity (Scheme 140). The complete diastereoselectivity was attributed to the ability of the pro-R oxetane transition structure to form bidentate chelation between the oxygen of the oxetane ring and the oxygen of the central ring to the Ag(I) salt (Scheme 140). This stabilization is not available to the pro-S transition structure. (520) The undesired spiroketal was readily epimerized by use of ZnCl₂ and MgO.

Scheme 140. Oxetane Ring-Opening Step in Total Synthesis of Ascospiroketal

8.1.2 Enantioselective Ring Opening

Tomioka and co-workers (522) reported the first example of enantioselective desymmetrization of 3-substituted oxetanes, in 1997, by treatment with organolithium reagents. 3-Phenyloxetane was treated with PhLi, stoichiometric BF₃·OBu₂, and an external chiral tridentate ligand 354 at −78 °C to afford chiral alcohol 355 in a yield of 92% and ee of 47% (Scheme 141). n-Butyllithium and lithum phenylacetylide also successfully gave the corresponding alcohols in good yields but with low ee values of 27% and 15%, respectively.

Scheme 141. Enantioselective Ring Opening of 3-Substituted Oxetanes with Stoichiometric Chiral Ligand

Catalytic enantioselective ring opening of 3-substituted oxetanes, by use of 2-mercaptobenzothiazoles 356 as nucleophiles with chiral phosphoric acid catalyst 358, was reported in 2013 by Sun and co-workers (8, 289) (Scheme 142). Substituted and unsubstituted mercaptobenzothiazoles were used and could generate tertiary or quaternary chiral centers in the products 357. Low catalyst loadings of 2.5 mol % were employed, and broadly excellent enantioselectivities of 71–99% ee were obtained.

Scheme 142. Enantioselective Ring Opening of 3-Substituted Oxetanes with Mercaptobenzothiazoles

In 2009, Loy and Jacobsen (523) reported the intramolecular enantioselective ring opening of 3-substituted and 3,3-disubstituted oxetanes catalyzed by Co–salen complex 359 or 360 (Scheme 143). Bimetallic catalyst 360 (n = 1) showed enhanced reactivity compared to monomeric catalyst 359, likely due to cooperative interaction between (salen)Co motifs. Tetrahydrofurans were formed in high yields of 89–93% and excellent ee values (96–99%) when oligomeric catalyst 360 was employed (Table 31). Alkyl and phenyl substitution at the 3-position of oxetane was tolerated under the reaction conditions, affording THFs with quaternary stereocenters. Phenolic substrates were also tolerated; however, a higher catalyst loading was required to attain good enantioselectivity.

Scheme 143. Co-Catalyzed Intramolecular Ring Opening of 3-Substituted Oxetanes

Table 31. Scope of Enantioselective Intramolecular Ring-Opening Reaction of 3-Substituted and 3,3-Disubstituted Oxetanes

Sun and co-workers (8) have recently reported several examples of intramolecular enantioselective oxetane ring opening. In 2013, the intramolecular ring opening of oxetanes to access chiral 1,2,3,4-tetrahydroisoquinolines was described (Scheme 144). (524) Reaction of aldehydes 361 with anilines in the presence of a Hantzsch ester (364) and enantiopure chiral phosphoric acid 363 afforded tetrahydroisoquinolines 362 in excellent yields and high enantioselectivities. This reaction was successful with a range of electron-donating and electron-withdrawing aryl aldehydes. With 3,3-disubstituted oxetanes, the product with a quaternary center (365) was formed with an excellent yield of 94% but moderate enantioselectivity (56% ee).

Scheme 144. Asymmetric Ring Opening of 3-Substituted Oxetanes by Use of Aromatic Amines and Chiral Phosphoric Acid Catalyst

By a similar principle, Sun and co-workers (525) reported the asymmetric three-component aza-Diels–Alder reaction of indoles using a chiral phosphoric acid catalyst and an oxetane ring as the directing group. Oxetane-tethered aldehydes 366 were combined with indoles 367 and arylamines 368 in the presence of catalyst 363 to afford a variety of polycyclic alkaloid-like products 369 (Table 32).

Table 32. Catalytic Asymmetric Multicomponent Aza-Diels–Alder Reaction

Yang and Sun (526) described the enantioselective synthesis of 1,4-dioxanes via intramolecular desymmetrization of oxetanes in 2016. 3,3-Disubstituted oxetanes 370 were treated with a chiral phosphoric acid catalyst 372 of the same type to access chiral 1,4-dioxanes 371 bearing a quaternary stereocenter (Table 33). Alkyl and aryl substituents were tolerated as substituents at the 3-position of the oxetane ring; however, the presence of a trifluoromethyl substituent retarded the reaction, and an increase in temperature was required to obtain conversion. Increased steric hindrance in close proximity to the alcohol functional group did not affect the reaction efficiency or enantioselectivity. When the oxygen atom in the side chain was replaced with a carbon atom (373), other oxaheterocycles 374 were synthesized in yields of 89–94% and ee values of 68–91% (Scheme 145). Very recently, the same group reported an enantioselective opening of 3-substituted oxetanes, with chloride as a nucleophile, to generate functionalized γ-chlorohydrins. (527) Trimethoxychlorosilane was used as the chloride source in the presence of wet molecular sieves for a controlled release of HCl.

Table 33. Enantioselective Synthesis of 1,4-Dioxanes via Oxetane Desymmetrization

entry	R	R′	cat loading (mol %)	time (h)	yield 371 (%)	ee (%)
1	Me	H	2	12	93	98
2	iPr	H	3	36	95	92
3^a	CF₃	H	10	60	92	98
4	HO(CH₂)₄	H	5	12	99	97
5	vinyl	H	5	8	93	96
6	allyl	H	3	12	89	98
7	Ph	H	5	30	98	92
8	Me	Me	5	12	92	94

Reaction was run at 60 °C.

Scheme 145. Enantioselective Synthesis of Alternative Oxaheterocycles

8.1.3 Ring Opening of Oxetan-3-one Derivatives

The last five years has seen reports of the conversion of oxetan-3-one to a variety of heterocycles. Carreira and co-workers (528) developed a formation of isoxazoles via a base-mediated rearrangement of 3-(nitromethylene)oxetanes. The use of iPr₂EtN in THF resulted in clean conversion to the isoxazole. This was proposed to occur by deprotonation of the oxetane to form a strained oxetene intermediate, which could undergo ring opening by the nitronate anion followed by dehydration to furnish the isoxazole-4-carboxaldehyde 375. A one-pot cascade reaction was then successfully developed, starting with a Henry reaction between (2-nitroethyl)benzene and oxetan-3-one (Scheme 146). Subsequent mesylation and elimination of the corresponding oxetan-3-ol, and then rearrangement, furnished the 3-benzylisoxazole-4-carboxaldehyde. The scope of the isoxazole-4-carboxaldehyde products at the 3-postion was quite varied. The phenyl group could be replaced with electron-rich and electron-deficient aromatic and heteroaromatic groups, aliphatic groups, remote esters, and terminal alkenes, as well as protected alcohols and amines. Aryl substitution at the 3-position was also viable starting from arylnitromethanes.

Scheme 146. Cascade Formation of Isoxazoles by Rearrangement of Oxetanes

Carreira and co-workers (529) generated a series of morpholines, thiomorpholines, and piperazines from oxetan-3-one via N,O-, N,S-, and N,N-acetals derived from oxetan-3-one. (529) The acetals were treated with TMSCN in the presence of catalytic indium triflate to form saturated nitrogen-containing heterocycles (Table 34). This involved a Strecker reaction with TMSCN to introduce the nitrile and then activation of the oxetane by the Lewis acid to promote intramolecular cyclization, which proceeded in excellent yields and dr. (529)

Table 34. Conversion of Oxetan-3-one into Saturated Nitrogen Heterocycles via Formation of Intermediate Spirocycles

entry	X	R	R¹	yield (%)	dr
1	O	H	iPr	92	>20:1
2	O	H	Me	80	>20:1
3	O	H	Ph	97	>16:1
4	O	Et	H	80
5	O	Ph	H	79
6	NTs	H	Et	67
7	S	H	H	41
8	S	Bn	Bn	89	2:1

Reaction of trifluoroborate nucleophiles with similar N,O-acetals, promoted by BF₃·OEt₂, generated aminooxetanes (see Scheme 79, section 5). (352) These products were shown to undergo ring opening to produce substituted morpholine rings. This two-step process could also be performed in one pot; for example, aminals 376 were converted to benzomorpholines 377 by employing an excess of BF₃·OEt₂ with substituted alkynyl potassium trifluoroborates (Table 35).

Table 35. One-Pot Ring Expansion of Spirocyclic Oxetanes

entry	R	yield 377 (%)
1	p-Cl-C₆H₄	85
2	Ph	69
3	H	81
4	TMS	75
5	Cy	64
6	(CH₂)₃Cl	82

Orr and co-workers (530) reported the microwave-mediated condensation of oxetan-3-one with primary amides or thioamides to afford (hydroxymethyl)oxazoles 378 and (hydroxymethyl)thiazoles 379 (Table 36). A range of aromatic substituents as well as tertiary and secondary alkyl groups were tolerated under the reaction conditions. The mechanism was proposed to involve first the opening of oxetan-3-one, followed by condensation.

Table 36. Microwave-Mediated Synthesis of Oxazoles and Thiazoles

		yield (%)
entry	R	378, X = O	379, X = S
1	Ph	36	64
2	cyclohexyl	17	63
3	tBu	14	40
4	3-F₃C-Ph	24	36
5	4-MeO-Ph	15	50

8.2 Ring-Expansion Reactions of Oxetanes

There have been investigations over many years into the ring expansion of oxetanes to generate larger oxygen heterocycles. In particular, oxetanes react with diazo compounds, which can afford mixtures of products resulting from ring expansion and ylide formation with protonation or rearrangement. (531, 532) In the 1960s, Nozaki et al. (533, 534) found that, when treated with a diazo compound in the presence of a chiral copper chelate, 2-phenyloxetane would undergo ring expansion to give a mixture of cis/trans THF derivatives. In 1994, Ito and Katsuki (535) reported asymmetric ring expansion of oxetanes to THFs. Aryl oxetanes were treated with t-butyl diazoacetate in the presence of a chiral bipyridyl Cu complex to afford the THFs in yields of 31–40%. Interestingly, whereas racemic 2-(phenyl)oxetane afforded a 1:1 mixture of trans- and cis-t-butyltetrahydrofuran-2-carboxylates, (R)-2-phenyloxetane preferentially afforded the trans isomer while reaction with (S)-2-phenyloxetane afforded the cis isomer preferentially. (536-539)

In 2001, Lo and Fu (111) published conditions for asymmetric ring expansion of oxetanes to THFs using diazo esters in the presence of a Cu(I)/bis(azaferrocene) catalyst, giving excellent diastereo- and enantiocontrol over the newly generated stereocenter (Scheme 147). Both the cis and trans diastereoisomers could be synthesized simply by swapping the enantiomer of the bis(azaferrocene) ligand [(R,R)-381 gave trans-380 in 98% ee, while (S,S)-381 gave cis-380 in 95% ee].

Scheme 147. Asymmetric Ring Expansion of 2-Aryloxetanes by Use of Cu(I)/Bis(azaferrocene) Catalyst

Lacour and co-workers (540) described the formation of a number of interesting functionalized 15-membered macrocycles via Rh-catalyzed condensation of a single α-diazo-β-keto ester with three oxetane molecules (Scheme 148). The reaction proceeded under mild conditions at 20 °C, with catalyst loading of just 1 mol % Rh₂(OAc)₄ and oxetane as the solvent, forming the macrocycle in yields up to 84%. Different ester substituents were well-tolerated (R¹ = Me, Et, tBu, allyl; R² = Me), as were different ketone substituents (R² = Et, Pr, Ph, iPr; R¹ = Et), giving excellent yields (55–84%) of the macrocylic products (382). Substituted oxetanes such as 3,3′-dimethyl- and 3,3′-diethyloxetanes could be used to form the corresponding substituted macrocycles in 65% and 51% yield, respectively. The reaction was proposed to proceed via initial addition of oxetane oxygen to the Rh-carbenoid, generated from the α-diazo-β-keto ester, to form an oxetane ylide (383, Scheme 148). This oxetane unit then propagates the reaction through the electrophilic carbon at the oxetane 2-position, with two further oxetane units adding before trapping with the keto carbonyl becomes favored to furnish the macrocycle.

Scheme 148. Macrocyclization of Oxetanes with α-Diazo-β-keto Esters

In 1999, Larksarp and Alper (541) reported the cycloaddition of vinyloxetanes with heterocumulenes as a method to access 1,3-oxazines. 2-Vinyloxetane 384 was reacted with an isocyanate or a carbodiimide in the presence of palladium(0) catalyst and a phosphine ligand (Scheme 149). Alper proposed that the reaction proceeded via a π-allyl palladium intermediate, formed by addition of the vinyloxetane to the palladium complex, followed by reaction with the isocyanate or carbodiimide. The reaction yields were lower when isocyanates were used, possibly due to a faster rate of dimerization of the isocyanate than the rate of dimerization of carbodiimide, relative to the rate of cyclization. Bicyclic oxazines could be accessed from the cycloaddition of bicyclic vinyl oxetanes with isocyanates or carbodiimides but required a pressurized reactor.

Scheme 149. Synthesis of 1,3-Oxazines via Cycloaddition of Vinyloxetanes with Isocyanates or Carbodiimides

Njardarson and co-workers (542) have reported the ring expansion of vinyl-substituted oxetanes 385 in the presence of diazo compounds 386 and catalytic Cu(tfacac)₂. Both the [2,3] ring-expansion product 387 and the [1,2] insertion product 388 were observed in good combined yields, with the product ratio dependent on which diazo substrate was used (Scheme 150). The formation of an oxonium ylide intermediate was crucial for formation of both products.

Scheme 150. Ring Expansion of Vinyloxetanes to Medium-Sized Oxacycles

In subsequent studies, Njardarson and co-workers (543-546) reported the ring expansion of vinyloxetanes 389 to 3,6-dihydro-2H-pyrans 390 in the presence of 1 mol % Cu(OTf)₂ or 10 mol % triflic acid. Njardarson proposed that Cu(OTf)₂ coordinated to the oxetane oxygen atom, prompting ring opening, and the resulting allylic cation was then captured by the oxygen atom in a 6-endo-trig cyclization. When a chiral phosphoric acid catalyst 392 was employed, a chiral dihydropyran 391 was synthesized with 90% ee but in reduced yield (Scheme 151).

Scheme 151. Ring Expansion of Vinyloxetanes to 3,6-Dihydro-2H-pyrans

Treating vinyl oxetane 393 with diisopropyl dithiophosphate resulted in nucleophilic ring opening to form 394 with Z-selectivity, while a less nucleophilic reagent, diethyl phosphoric acid, resulted in ring expansion to form the six-membered ring 395 (Scheme 152). (547) Sterics played an important role in this reaction, with substituents at the olefin terminus inhibiting the nucleophilic ring opening and enhancing the acid-catalyzed pathway to form the ring-expanded product. No reaction was observed when alkynyloxetanes were exposed to the reaction conditions.

Scheme 152. Z-Selective Ring Opening and Ring Expansion of Vinyloxetanes

Alkynyloxetanes have been used in metal-catalyzed oxidative cyclization reactions. Gagosz and co-workers (548) showed that when alkynyloxetane 396 was treated with a Cu(I) catalyst in the presence of an oxidant, ring expansion occurred to form both dihydrofuran 397 and lactone 398 (Table 37). Careful tuning of the substituents on the pyridine N-oxide promoted selective formation of either product. The use of a more electron-deficient 3-bromopyridine N-oxide favored dihydrofuran formation, being a better leaving group for 5-exo-trig cyclization (entry 2). The more electron-rich 4-methoxypyridine N-oxide favored lactone formation (entry 3). This ring expansion was successful with a variety of alkynyloxetanes, including both aryl and alkyl substitution at the 2-position as well as methyl and phenyl groups at the 3-position of the oxetane ring.

Table 37. Cu(I)-Catalyzed Ring Opening of Alkynyloxetane 396 to Lactone and Dihydrofuran

entry	R	ratio (397:398)	yield (%)
1	H	1.9:1	84
2	3-Br	1:0	85
3	4-OMe	0:1	74

Formation of eight-membered heterocycles via Ni-catalyzed reaction of oxetan-3-ones with 1,3-dienes was reported by Louie and co-workers in 2013. (549) Oxetan-3-one was treated with 1,3-dienes in the presence of Ni(cod)₂ and P(p-tolyl)₃ to afford medium-sized rings (Scheme 153). The methodology was also successful in reaction of azetidin-3-ones with 1,3-dienes to form eight-membered N-heterocycles. Dienes with benzyl and homobenzyl substituents were well-tolerated under the reaction conditions, as were macrocyclic dienes.

Scheme 153. Nickel-Catalyzed Cycloaddition of 1,3-Dienes with Oxetan-3-ones and Azetidin-3-ones

In 2014, Liu and co-workers (550) reported the [4 + 2] cycloaddition of ynamides 399 with 2-aryloxetanes in the presence of an Ag/Au complex to afford six-membered 6-amino-3,4-dihydro-2H-pyrans 400 (Scheme 154). Excellent regioselectivity was observed due to the electrophilicity of the Au−π-ynamides, which react with the oxetane nucleophiles. (550) A variety of aryloxetanes and arylynamides were successfully employed in the cycloaddition reaction.

Scheme 154. Au- and Ag-Catalyzed [4 + 2] Cycloaddition of Ynamides with Oxetanes^a

In 2014, Yin and You (551) reported an enantioselective chlorination/ring-expansion cascade of cyclobutanols, accessing chiral 2-alkyl-2-aryl cycloalkanones with excellent ee values by use of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), (DHQD)₂PHAL as a catalyst, and N-Boc-l-phenylglycine (NBLP) as a ligand. Yin and You also showed that oxetanols 401 were also compatible with this methodology, accessing enantioenriched dihydrofuran-3(2H)-ones 402 in good yields and excellent enantioselectivities (Scheme 155). Substrates bearing halogenated aryl rings showed decreased reactivity compared with more electron-donating substituted aromatics.

Scheme 155. Asymmetric Chlorination/Ring Expansion of Oxetanols

9 Conclusion

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This review aims to provide an overview of the extensive recent works involving oxetanes in synthesis and medicinal chemistry and to highlight the continuing challenges. This interest has been facilitated, and partly driven, by the emergence of oxetanes for applications in medicinal chemistry. Oxetanes present important opportunities to tune physicochemical properties and increase the stability of a molecule, as well as providing intellectual property novelty within a compact motif. Thanks to the increasing commercial availability of oxetane-containing building blocks, along with improved methods for synthesis, oxetanes are likely to be increasingly used in medicinal chemistry programs. However, to date it remains challenging to target specific oxetane derivatives and to position substituents and functional groups around the ring at prescribed locations, especially for chiral nonracemic oxetanes. These synthetic challenges continue to limit the full exploitation of this ring system.

Williamson etherification remains the most common approach for oxetane synthesis, with cyclization from 1,4-functionalized precursors providing a reliable strategy. However, the functionality that can be installed on the ring by this approach is sometimes limited, and the synthesis of (enantioenriched) cyclization precursors presents its own challenge. An epoxide-opening and ring-closure sequence with sulfoxonium ylides can take advantage of chiral epoxide precursors to generate enantioenriched oxetanes. Sugars are also valuable precursors to oxetanes but can require lengthy sequences to unveil the heterocycle, with the stereochemical outcome determined by the starting sugar. Alternative C–C bond-forming cyclization methods are emerging that offer the potential to access new and valuable derivatives in relatively short sequences and to provide oxetanes bearing more varied functional groups. Increasing the options for cyclization through alternative strategies that are applicable to a wide array of substrates would be a valuable addition to the current methodology.

The Paternò–Büchi reaction continues to present a conceptually attractive approach to bring together readily available reactive partners to form oxetane rings. The substituent requirements for photochemical activation have perhaps limited the application of this methodology in medicinal chemistry to date. However, this reaction presents considerable scope for further development, likely to exploit technological developments and engineering solutions to facilitate the photochemistry. At the same time, small-molecule-catalyzed formal [2+2] methods offer a compelling alternative, especially where chiral catalysts can be exploited to generate enantioenriched products. The scope of recent developments has been limited to highly electrophilic ketones, such as trifluoromethyl ketones and closely related derivatives, but offers considerable potential upon extension to wider classes of reagents.

One approach to access oxetane derivatives likely to see extensive development in coming years is the functionalization of intact oxetane rings, taking advantage of preformed oxetane derivatives as building blocks and also allowing divergent synthesis. To date this is not well-developed, with few bond-forming reactions available, although S_N2 reactions have been demonstrated by use of good nucleophiles on oxetanes bearing leaving groups. There is considerable potential for the application of more (stereocontrolled) methods to attach oxetane derivatives to target structures. Carreira’s oxetanone has been widely embraced by synthetic and medicinal chemistry communities, with simple reactions such as reductive amination being very popular, as well as having applications in more complex ketone chemistry and multicomponent reactions. Simple cross-couplings of other oxetane units, such as halide and boronic acid derivatives, are not well-developed, but some important examples of cross-coupling at the oxetane 3-position include Negishi cross-couplings and reductive coupling of an oxetane halide with an aryl halide component. Furthermore, only monosubstituted oxetane derivatives have been demonstrated in these cross-coupling reactions.

Attempts to deprotonate oxetanes and form oxetanyl anions have been limited to date, presumably due to the reactive carbenoid nature of the deprotonated intermediate, and stabilizing groups have been required in these limited examples. Complementary radical methods have emerged recently by use of oxetane itself. While these approaches have often used a large excess of oxetane reagent, there is considerable potential for method development and application to a wider range of oxetane structures.

2-exo-Methyleneoxetanes present interesting precursors for further reaction and another strategy to introduce groups onto the oxetane ring, through activation of the olefin and addition of nucleophiles. Subtle reactivity differences between nucleophiles can lead to different outcomes, potentially with ring opening as a competing reaction pathway. Enantioselective syntheses of alkylideneoxetanes have recently emerged through formal [2+2] methods from allenes and ketones, with the reaction scope to date limited to activated ketones.

The wide variety and number of oxetane compounds appearing in the medicinal chemistry and patent literature highlights the breadth of occurrence and the advantages perceived from incorporation of this motif. Most commonly, 3-substituted oxetane derivatives are observed in these potential medicinal compounds, being derived from simple building blocks; 3-amino and 3-mono- or 3,3-disubstituted oxetane derivatives (alkyl–alkyl or aryl–alkyl) are most prevalent. Occasionally 2-substituted derivatives have been made, though there are fewer available building blocks, and these derivatives can introduce chirality and hence complexity. Nucleoside analogues, containing fused and spirocyclic oxetanes, have also shown interesting activity and profiles. However, it is apparent that the oxetane structures are most commonly present as pendant motifs. Further growth in the numbers of simple, small oxetane building blocks that are readily available and can be readily incorporated through simple linkages would certainly be welcomed by medicinal chemists. Such small motifs, without additional functionality to utilize in synthesis, are not trivial to prepare in large quantities through current methods.

There continue to be important questions on the stability of the oxetane motif in biological settings, which is crucial information in the context of medicinal chemistry. In many cases, high stability has been observed; however, this is likely to be dependent on specific cases and surrounding molecular structure and functional groups, and more studies are required. For acid stability and stability to nucleophiles, a greater understanding of structure–stability relationships, including the effect of different substituents and substitution patterns on the oxetane ring, as well as the effects of other groups in the molecule that may have stabilizing or destabilizing effects, would be very valuable. Such precompetitive information could facilitate the more targeted installation of appropriate oxetane derivatives, and the design of new derivatives that may offer improved properties. On the other hand, the small ring, being unusual and not well recognized by the body, is unlikely to present specific metabolic liabilities. Indeed, the beneficial increase in polarity upon incorporation of an oxetane provides a general reduction of lipophilicity, often associated with an increase in metabolic stability.

Oxetanes present considerable potential as isosteres. To date, the majority of studies from Carreira concerned the replacement of gem-dimethyl groups or carbonyl groups; replacement of the carbonyl of thalidomide with an oxetane to prevent racemization provides an elegant example. Peptide mimics have recently appeared in the literature, in the form of aminooxetanes, which show stability to enzymatic cleavage. Other specific isosteres can be envisaged that could offer attractive properties, for example, specific ester or ketone derivatives, which could be examined through direct pairwise comparison. Furthermore, novel substituted oxetane derivatives can readily provide access to new chemical space. More data will inevitably emerge as usage in medicinal chemistry continues and as new attractive building blocks and methods facilitate further use, contributing to the body of knowledge on the appropriateness of the oxetane ring in different circumstances.

Powerful examples of the use of oxetanes as intermediates in the synthesis of complex molecules and natural products have been reported in the last five years. Exploitation of oxetanes as reactive intermediates in this way provides a valuable disconnection that is likely to be exploited more widely. However, there remains space for fundamental studies on methods for the ring opening of oxetanes. As a synthon, oxetane is not yet close to being afforded a similar profile in ring-opening reactions as the analogous epoxide, but it offers similar potential. The opening of enantioenriched oxetanes provides valuable chiral building blocks, but nucleophilic opening remains underexplored.

On the other hand, enantioselective opening of prochiral oxetanes has taken great strides, through the desymmetrization of prochiral 3-substituted and 3,3-disubstituted oxetanes. Very high ee values have been obtained, and there are clear opportunities for further development to extend the range of nucleophiles and substrates, as well as to applying these strategies to additional transformations that generate complexity. Furthermore, the development of enantioselective kinetic resolutions of racemic chiral derivatives would present alternative approaches to enantioenriched building blocks.

It is feasible that improved understanding of oxetane ring opening could lead to applications in medicinal chemistry, for example, as covalent irreversible inhibitors with an oxetane “warhead”. Alternatively, as a labeling tool in chemical biology, subtle changes in oxetane structure may be able to promote selective reactions, for example, with protein side chains.

Throughout this review, we have considered applications toward biologically active compounds and medicinal chemistry. Undoubtedly, improved access to oxetane derivatives and understanding of ring opening will have impact in other fields, such as polymer and materials science, through bespoke oxetane monomers. The development of shorter and stereocontrolled routes to oxetane derivatives, bearing a greater variety of functionality around the ring, as well as novel readily accessible oxetane building blocks, are required to develop the applicability of the four-membered ring in these and other fields. Numerous challenges remain in synthesis, reactivity, and understanding of oxetane properties, but we expect further exciting developments in coming years.

Author Information

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Corresponding Author
- James A. Bull - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom; Email: [email protected]
Authors
- Rosemary A. Croft - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
- Owen A. Davis - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
- Robert Doran - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
- Kate F. Morgan - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
Notes
The authors declare no competing financial interest.

Biographies

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James A. Bull is a University Research Fellow in the Department of Chemistry at Imperial College London. He obtained his M.Sci. degree from University of Cambridge, then spent a year at GlaxoSmithKline. He returned to University of Cambridge to obtain his Ph.D. in organic chemistry under the supervision of Professor Steven V. Ley (2006). He then spent two years undertaking postdoctoral research with Professor André B. Charette at Université de Montréal. In 2009 he joined Imperial College London as a Ramsay Memorial Research Fellow. In 2011 he was awarded an EPSRC Career Acceleration Fellowship on strategies to access novel heterocycles of interest in drug discovery. In 2016 he was awarded a University Research Fellowship from The Royal Society.

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Rosemary A. Croft received her M.Sci. degree in 2014 from the University of Bristol, having completed her final-year research project working on carbonylative ring-expansion methodology. She was awarded an Imperial College Scholarship and moved to Imperial College London in October 2014 to commence a Ph.D under the supervision of Dr James Bull. Her project is focused on the synthesis and derivatization of novel oxetane scaffolds of particular interest to the pharmaceutical industry.

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Owen A. Davis received his first-class honours M.Sci. degree in chemistry from Imperial College London in 2012. He then continued his Ph.D. studies at Imperial College, where he was awarded an EPSRC DTG scholarship with Dr. James Bull. His Ph.D. studies focused on the synthesis and functionalization of highly substituted oxetanes and other small-ring heterocycles. In 2016, he joined the Institute of Cancer Research in a postdoctoral position in the group of Dr. Swen Hoelder.

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Robert Doran, from County Wicklow, Ireland, graduated from University College Dublin (UCD) in 2010 with a first-class honours B.Sc. degree in chemistry. He was awarded an Embark postgraduate scholarship from the Irish Research Council in 2010 to undertake Ph.D. studies with Professor Patrick J. Guiry at UCD on the total synthesis of lactone-containing natural products and catalytic asymmetric synthesis of α-aryl ketones. He received his Ph.D. in 2014, after which he moved to the group of Dr James A. Bull at Imperial College London for postdoctoral studies on the synthesis and functionalization of oxetanes and sulfoximines.

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Kate F. Morgan graduated from St. Andrews University in 2010 with a first-class M.Chem. degree in chemistry with an industrial placement. Her final-year project was based on synthesis of glucosinolates, under the supervision of Dr. Nigel Botting. In 2011 she moved to London to undertake Ph.D. studies, sponsored by AstraZeneca, in organic chemistry under the supervision of Dr. James Bull. She was awarded a Ph.D. in 2015 for her work on the synthesis and functionalisation of oxetanes. In 2015 she moved to the Royal Society as a grants scheme manager.

Acknowledgment

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We are grateful for funding to EPSRC (CAF, EP/J001538/1; Impact Acceleration Account, EP/K503733/1), The Royal Society (University Research Fellowship to J.A.B.), and Imperial College London.

References

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Recent progress regarding regio-, site-, and stereoselective formation of oxetanes in Paterno-Buechi reactions
Abe, Manabu
Journal of the Chinese Chemical Society (Taipei, Taiwan) (2008), 55 (3), 479-486CODEN: JCCTAC; ISSN:0009-4536. (Chinese Chemical Society)
A review. Recently, the demand for synthetic oxetanes has increased because the highly strained structure allows specific biol. functions in vivo and also serves unique purposes in industrial materials. This review article summarizes recent progress in regio-, site-, and stereo-selective formation of oxetanes via a photochem. process.
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D’Auria, M.; Racioppi, R. Oxetane Synthesis Through the Paternò-Büchi Reaction Molecules 2013, 18, 11384– 11428 DOI: 10.3390/molecules180911384
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Oxetane synthesis through the Paterno-Buchi reaction
D'Auria, Maurizio; Racioppi, Rocco
Molecules (2013), 18 (9), 11384-11428CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
A review. The Paterno-Buchi reaction is a photochem. reaction between a carbonyl compd. and an alkene to give the corresponding oxetane. The reaction mechanism is discussed and reaction with electron rich alkenes (enolethers, enol esters, enol silyl ethers, enamines, heterocyclic compds.) has been reported. The stereochem. behavior of the reaction is particularly stressed. The reported applications of this reaction to the synthesis of naturally occurring compds is also discussed.
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Dejaegher, Y.; Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe, N. The Chemistry of Azetidin-3-ones, Oxetan-3-ones, and Thietan-3-ones Chem. Rev. 2002, 102, 29– 60 DOI: 10.1021/cr990134z
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The Chemistry of Azetidin-3-ones, Oxetan-3-ones, and Thietan-3-ones
Dejaegher, Yves; Kuz'menok, Nina M.; Zvonok, Alexander M.; De Kimpe, Norbert
Chemical Reviews (Washington, D. C.) (2002), 102 (1), 29-60CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review with 254 refs.
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Mahal, A. Oxetanes as Versatile Building Blocks in the Total Synthesis of Natural Products: An Overview Eur. J. Chem. 2015, 6, 357– 366 DOI: 10.5155/eurjchem.6.3.357-366.1267
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Oxetanes as versatile building blocks in the total synthesis of natural products: an overview
Mahal, Ahmed
European Journal of Chemistry (2015), 6 (3), 357-366CODEN: EJCUA9; ISSN:2153-2249. (European Journal of Chemistry)
A review. Oxetane ring plays an important role as main core in naturally occurring compds. and has many applications in pharmaceutical industries and synthetic org. chem. In this review, we report a brief survey of using the oxetane ring as versatile precursors in the total synthesis of natural products. Many approaches such as cyclization, addn., oxidn., redn., elimination, protection as well as deprotection reactions utilized to synthesize of most important oxetane-contg. natural products involving taxol, (±)-merrilactone A, (±)-oxetin, L-oxetanocin, (+)-(Z)-laureatin and L-oxetanocin are also covered. We describe in this review the most common total synthesis approaches have been yet applied to synthesis of most important oxetane-contg. natural products. The review is also included isolation, structure identification of these oxetane-contg. natural products. The biol. activity of oxetane-contg. natural products due to the oxetane ring is also defined.
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Malapit, C. A.; Howell, A. R. Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds J. Org. Chem. 2015, 80, 8489– 8495 DOI: 10.1021/acs.joc.5b01255
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Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds
Malapit, Christian A.; Howell, Amy R.
Journal of Organic Chemistry (2015), 80 (17), 8489-8495CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A review. Oxetanes are valuable intermediates in org. synthesis, and strategic manipulations of this strained heterocycle continue to emerge. In this Synopsis, recent, distinct approaches to construct heterocyclic systems using oxetanes are described. These include ring expansion, ring opening, and C-2 functionalization.
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Wang, Z.; Chen, Z.; Sun, J. Catalytic Asymmetric Nucleophilic Openings of 3-Substituted Oxetanes Org. Biomol. Chem. 2014, 12, 6028– 6032 DOI: 10.1039/C4OB00920G
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Catalytic asymmetric nucleophilic openings of 3-substituted oxetanes
Wang, Zhaobin; Chen, Zhilong; Sun, Jianwei
Organic & Biomolecular Chemistry (2014), 12 (32), 6028-6032CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A review. Asym. ring-opening of 3-substituted oxetanes provides rapid access to highly functionalized chiral building blocks. However, progress in this field is limited. Recently the authors developed a new catalytic system based on chiral Bronsted acids for this type of reaction and demonstrated the synthesis of a range of useful mols. under mild and operationally simple conditions. In this perspective, the authors describe the challenges, progress, and potential future efforts on this topic.
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Hailes, H. C.; Behrendt, J. M. Oxetanes and Oxetenes: Monocyclic. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K., 2008; Vol. 2, Chapt. 2.05, pp 321– 364; DOI: DOI: 10.1016/B978-008044992-0.00205-4 .
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Dussault, P. H.; Xu, C. Oxetanes and Oxetenes: Fused-ring Derivatives. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K., 2008; Vol. 2, Chapt. 2.06, pp 365– 387; DOI: DOI: 10.1016/B978-008044992-0.00206-6 .
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Alcaide, B.; Almendros, P. Four-Membered Ring Systems. In Progress in Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A., Eds.; Elsevier: New York, 2011; Vol. 23, Chapt. 4, pp 101– 125; DOI: DOI: 10.1016/B978-0-08-096805-6.00004-8 .
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Kudo, H.; Nishikubo, T. Catalytic Reactions of Oxetanes with Protonic Reagents and Aprotic Reagents Leading to Novel Polymers J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 709– 726 DOI: 10.1002/pola.21828
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Catalytic reactions of oxetanes with protonic reagents and aprotic reagents leading to crosslinked and hyperbranched polymers
Kudo, Hiroto; Nishikubo, Tadatomi
Journal of Polymer Science, Part A: Polymer Chemistry (2007), 45 (5), 709-726CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
A review. This paper reports new addn. reactions of oxetanes with certain protonic reagents such as carboxylic acid, phenol, and thiol, and with certain aprotic reagents such as acyl chloride, thioester, phosphonyl dichloride, silyl chloride, and chloroformate using quaternary onium salts as catalysts. The kinetic study of the addn. reactions of oxetanes was also studied. These new addn. reactions were applicable to the synthesis of new polymers. These polyaddn. systems could also construct both polymer main chains and reactive side chains. The alternating copolymn. of oxetanes with carboxylic anhydride was performed. Also, anionic ring-opening polymn. of oxetanes contg. hydroxy groups proceeded to afford the hyperbranched polymer (HBP) with an oxetanyl group and many hydroxy groups at the ends of the polymer chains. Alkali-developable photofunctional HBPs were synthesized by the polyaddn. of bis(oxetane)s or tris(oxetane)s, and their patterning properties were examd., too. The photo-induced cationic polymn. of the polymers with pendant oxetanyl groups and the thermal curing reactions of poly-functional oxetanes (oxetane resins) were also examd. to give the crosslinking materials quant.
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Schulte, B.; Dannenberg, C. A.; Keul, H.; Moeller, M. Formation of Linear and Cyclic Polyoxetanes in the Cationic Ring-Opening Polymerization of 3-Allyloxymethyl-3-Ethyloxetane and Subsequent Postpolymerization Modification of poly(3-Allyloxymethyl-3-Ethyloxetane) J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 1243– 1254 DOI: 10.1002/pola.26494
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Formation of linear and cyclic polyoxetanes in the cationic ring-opening polymerization of 3-allyloxymethyl-3-ethyloxetane and subsequent postpolymerization modification of poly(3-allyloxymethyl-3-ethyloxetane)
Schulte, Bjoern; Dannenberg, Carl A.; Keul, Helmut; Moeller, Martin
Journal of Polymer Science, Part A: Polymer Chemistry (2013), 51 (5), 1243-1254CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
The synthesis of 3-allyloxymethyl-3-ethyloxetane (AllylEHO) and its polymn. with BF3 × Et2O is described in this study. Size exclusion chromatog. (SEC) and membrane osmometry are used for the detn. of mol. wts. of the obtained products, ranging from Mn,SEC = 41,500-131,500 g/mol. 1H NMR spectroscopy, SEC, as well as MALDI-TOF MS reveal the formation of cyclic tetramer beside low, but detectable concns. of larger cyclic oligomers as byproducts during the polymn. process. These results help to understand mechanistically why attempts for a controlled homopolymn. of AllylEHO fail and why a controlled homopolymn. of oxetanes has not been described so far in the literature. Addnl., the high versatility of allyl-functional polyoxetane for postpolymn. modification is proven by thiol-ene reactions with 3-mercaptopropionic acid and N-acetyl-L-cysteine Me ester. cpr 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012.
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Christ, E. M.; Müller, S. S.; Berger-Nicoletti, E.; Frey, H. Hydroxyfunctional Oxetane-Inimers with Varied Polarity for the Synthesis of Hyperbranched Polyether Polyols via Cationic ROP J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2850– 2859 DOI: 10.1002/pola.27315
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Hydroxyfunctional oxetane-inimers with varied polarity for the synthesis of hyperbranched polyether polyols via cationic ROP
Christ, Eva-Maria; Mueller, Sophie S.; Berger-Nicoletti, Elena; Frey, Holger
Journal of Polymer Science, Part A: Polymer Chemistry (2014), 52 (19), 2850-2859CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
Synthesis and characterization of novel hydroxyl-functionalized oxetane-inimers with varied alkyl chain length-3-hydroxymethyl-3-methoxymethyloxetane, 3-hydroxymethyl-3-propoxymethyloxetane, and 3-hexyloxymethyl-3-hydroxymethyloxetane-is reported. Cationic ring-opening polymn. of these latent, cyclic AB2-monomers leads to hyperbranched (hb) polyether polyols with degrees of branching between 34 and 69%, confirmed by inverse-gated (IG) 13C NMR spectroscopy. The hyperbranching polymn. yielded apparent mol. wts. (Mn) ranging from 500 to 2500 g mol-1 (size exclusion chromatog.). Remarkably, by copolymn. of 1,1,1-tris(4-hydroxyphenyl)ethane as a "focal" unit, polymn. under slow monomer addn. conditions lead to higher apparent mol. wts. up to 11,220 g mol-1. The end groups of the hb polymers were studied via matrix-assisted laser desorption/ionization time of flight mass and NMR spectrometry. By varying the alkyl chain length, tailoring of the soly. and glass transition temps. of the materials is possible. Potential applications range from macroinitiators with defined polarity to tailoring of surface properties of antifouling materials. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014.
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Schulte, B.; Rahimi, K.; Keul, H.; Demco, D. E.; Walther, A.; Möller, M. Blending of Reactive Prepolymers to Control the Morphology and Polarity of Polyglycidol Based Microgels Soft Matter 2015, 11, 943– 953 DOI: 10.1039/C4SM02116A
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Kudo, H.; Morita, A.; Nishikubo, T. Synthesis of a Hetero Telechelic Hyperbranched Polyether. Anionic Ring-Opening Polymerization of 3-Ethyl-3-(hydroxymethyl)oxetane Using Potassium tert-Butoxide as an Initiator Polym. J. 2003, 35, 88– 91 DOI: 10.1295/polymj.35.88
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Synthesis of a hetero telechelic hyperbranched polyether. Anionic ring-opening polymerization of 3-ethyl-3-(hydroxymethyl)oxetane using potassium tert-butoxide as an initiator
Kudo, Hiroto; Morita, Ayako; Nishikubo, Tadatomi
Polymer Journal (Tokyo, Japan) (2003), 35 (1), 88-91CODEN: POLJB8; ISSN:0032-3896. (Society of Polymer Science, Japan)
The anionic ring-opening polymn. of 3-ethyl-(3-hydroxymethyl)oxetane (EHO) affording hetero telechelic hyperbranched polyethers contg. an oxetanyl and many OH-groups at the ends (poly(EHO)) is described. Polymn. of EHO was performed in presence of t-BuOK and 18-crown-6 in N-methylpyrrolidone. Polymn. outcome was detd. in dependence of reaction time and temp. (24, 48, and 168 h; 100, 120, 140, 160, 180°). The structure of dendritic poly(EHO) was elucidated and thermal properties were detd.
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Morita, A.; Kudo, H.; Nishikubo, T. Synthesis of Hyperbranched Polymers by the Anionic Ring-Opening Polymerization of 3,3-Bis(hydroxymethyl)oxetane Polym. J. 2004, 36, 413– 421 DOI: 10.1295/polymj.36.413
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Synthesis of hyperbranched polymers by the anionic ring-opening polymerization of 3,3-bis(hydroxymethyl)oxetane
Morita, Ayako; Kudo, Hiroto; Nishikubo, Tadatomi
Polymer Journal (Tokyo, Japan) (2004), 36 (5), 413-421CODEN: POLJB8; ISSN:0032-3896. (Society of Polymer Science, Japan)
The anionic ring-opening polymn. of 3,3-bis(hydroxymethyl)oxetane (BHO) was carried out using t-BuOK as an initiator in the presence of 18-crown-6-ether (18-C-6) in NMP at 180 °C, affording the corresponding hyperbranched polyethers, poly(BHO)s contg. an oxetanyl group and many hydroxyl groups at the ends in 83-98% yields. Since the resulting poly(BHO)s were insol. in common org. solvents, the poly(BHO)s were treated with acetic anhydride to obtain poly(BHO-Ac)s contg. acetyl groups at the ends. The Mns and degree of branching (DB) of poly(BHO-Ac)s were in the range of 2600-4400 estd. by SEC and 0.09-0.55 calcd. by 13C NMR spectroscopy, resp. The cationic copolymn. of poly(BHO-Ac) and 3-ethyl-3-phenoxymethyloxetane (EPO) was examd. using BF3OEt2 as an initiator in CHCl3 at 0 °C for 24 h, affording pseudo dendritic polymers, poly-[poly(BHO-Ac)/EPO]s with Mn = 11000-15000 in 58-65% yields. Furthermore, the obtained poly[poly(BHO-Ac)/EPO] was hydrolyzed with KOH to afford the poly[poly(BHO)/EPO] contg. many hydroxyl groups.
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Crivello, J. V. Kick-Starting” Oxetane Photopolymerizations J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2934– 2946 DOI: 10.1002/pola.27329
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"Kick-Starting" oxetane photopolymerizations
Crivello, James V.
Journal of Polymer Science, Part A: Polymer Chemistry (2014), 52 (20), 2934-2946CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
In the presence of small amts. of 2,2-dialkyl-, 2,2,3-trialkyl-, or 2,2,3,3-tetraalkyl substituted epoxides such as isobutylene oxide, 1,2-limonene oxide, and 2,2,3,3,-tetramethyloxirane, the photoinitiated cationic ring-opening polymns. of 3,3-disubstituted oxetanes are dramatically accelerated. The acceleration affect was attributed to an increase in the rate of the initiation step of these latter monomers. Both mono- and disubstituted oxetane monomers are similarly accelerated by the above-mentioned epoxides to give crosslinked network polymers. The potential for the use of such "kick-started" systems in applications such as coatings, adhesives, printing inks, dental composites and in three-dimensional imaging is discussed. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014.
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Ghosh, B.; Urban, M. W. Self-Repairing Oxetane-Substituted Chitosan Polyurethane Networks Science 2009, 323, 1458– 1460 DOI: 10.1126/science.1167391
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Self-Repairing Oxetane-Substituted Chitosan Polyurethane Networks
Ghosh, Biswajit; Urban, Marek W.
Science (Washington, DC, United States) (2009), 323 (5920), 1458-1460CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Polyurethanes have many properties that qualify them as high-performance polymeric materials, but they still suffer from mech. damage. We report the development of polyurethane networks that exhibit self-repairing characteristics upon exposure to UV light. The network consists of an oxetane-substituted chitosan precursor incorporated into a two-component polyurethane. Upon mech. damage of the network, four-member oxetane rings open to create two reactive ends. When exposed to UV light, chitosan chain scission occurs, which forms crosslinks with the reactive oxetane ends, thus repairing the network. These materials are capable of repairing themselves in less than an hour and can be used in many coatings applications, ranging from transportation to packaging or fashion and biomedical industries.
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Müller, S. S.; Frey, H. Synthesis of Oxetane-Functional Aliphatic Polyesters via Enzymatic Polycondensation Macromol. Chem. Phys. 2012, 213, 1783– 1790 DOI: 10.1002/macp.201200269
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Baba, A.; Kashiwagi, H.; Matsuda, H. Reaction of Carbon Dioxide with Oxetane Catalyzed by Organotin Halide Complexes: Control of Reaction by Ligands Organometallics 1987, 6, 137– 140 DOI: 10.1021/om00144a024
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Reaction of carbon dioxide with oxetane catalyzed by organotin halide complexes: control of reaction by ligands
Baba, Akio; Kashiwagi, Hiroki; Matsuda, Haruo
Organometallics (1987), 6 (1), 137-40CODEN: ORGND7; ISSN:0276-7333.
Complexes of organotin iodides with phosphines or phosphine oxides catalyze the addn. of CO2 to oxetane (I), giving trimethylene carbonate (II) and polycarbonate (III). The choice of a ligand is crucial. All the complexes with Bu3P gave III; the combination of Bu3SnI with Bu3P(O) gave II exclusively in good yields. The complex, Bu2SnI2·Bu3P(O), had no catalytic activity in the formation of either II or III from I. The coordination mode of ligands and the stability of the complexes are important. The function of ligands involves not only activation of the Sn/halogen bond but also the decrease in the acidity of the Sn compds., thus suppressing polymns.
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Darensbourg, D. J.; Moncada, A. I. (Salen)Co(II)/n-Bu₄NX Catalysts for the Coupling of CO₂ and Oxetane: Selectivity for Cyclic Carbonate Formation in the Production of Poly-(trimethylene Carbonate) Macromolecules 2009, 42, 4063– 4070 DOI: 10.1021/ma9002006
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(Salen)Co(II)/n-Bu4NX Catalysts for the Coupling of CO2 and Oxetane: Selectivity for Cyclic Carbonate Formation in the Production of Poly(trimethylene carbonate)
Darensbourg, Donald J.; Moncada, Adriana I.
Macromolecules (Washington, DC, United States) (2009), 42 (12), 4063-4070CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
The (salen)Co(II) complex ((1R,2R)-(-)-1,2-cyclohexanediamino-N,N'-bis(3,5-di-tert-butylsalicylidene)cobalt(II)) in the presence of an anion initiator, e.g. bromide, was a effective catalytic system for the coupling of oxetane and carbon dioxide, to provide the corresponding polycarbonate with minimal amt. of ether linkages. The mechanism of the coupling of oxetane and carbon dioxide was studied by in situ IR spectroscopy, where the first formed product is trimethylene carbonate (TMC). TMC is formed by a backbiting mechanism following ring-opening of oxetane by the anion initiator, subsequent to CO2 insertion into the cobalt-oxygen bond. The formation of the copolymer is shown to proceed mostly by way of the anionic ring-opening polymn. of preformed trimethylene carbonate in the presence of an anion in soln. Anions that are good leaving groups, i.e., bromide and iodide, are most effective at affording copolymer via this route. In the presence of greater than 2 equiv of anions the overall rate of copolymer prodn. is decreased, presumably due to inhibition of oxetane monomer binding to the cobalt center. However, under these conditions copolymer formation through ROP of TMC is enhanced, with mass spectral evidence found for the formation of a dimer of TMC.
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Darensbourg, D. J.; Horn, A., Jr; Moncada, A. I. A Facile Catalytic Synthesis of Trimethylene Carbonate from Trimethylene Oxide and Carbon Dioxide Green Chem. 2010, 12, 1376– 1379 DOI: 10.1039/c0gc00136h
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A facile catalytic synthesis of trimethylene carbonate from trimethylene oxide and carbon dioxide
Darensbourg, Donald J.; Horn, Adolfo, Jr.; Moncada, Adriana I.
Green Chemistry (2010), 12 (8), 1376-1379CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
The coupling of oxetane (trimethylene oxide) and carbon dioxide catalyzed by VO(acac)2 in the presence of an onium salt was studied. The process is highly selective and quant. for the prodn. of the six-membered cyclic carbonate, trimethylene carbonate, under very mild reaction conditions of 60 °C and 1.7 MPa. Other derivs. of trimethylene oxide similarly selectively afford the corresponding cyclic carbonates upon reaction with CO2.
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Buckley, B. R.; Patel, A. P.; Wijayantha, K. G. U. Selective Formation of Trimethylene Carbonate (TMC): Atmospheric Pressure Carbon Dioxide Utilization Eur. J. Org. Chem. 2015, 2015, 474– 478 DOI: 10.1002/ejoc.201403385
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Selective Formation of Trimethylene Carbonate (TMC): Atmospheric Pressure Carbon Dioxide Utilization
Buckley, Benjamin R.; Patel, Anish P.; Upul Wijayantha, K. G.
European Journal of Organic Chemistry (2015), 2015 (3), 474-478CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
Carbon dioxide utilization (CDU) is currently gaining increased interest due to the abundance of CO2 and its possible application as a C1 building block. We herein report the first example of atm. pressure carbon dioxide incorporation into oxetane to selectively form trimethylene carbonate (TMC), which is a significant challenge as TMC is thermodynamically less favored than its corresponding co-polymer.
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Whiteoak, C. J.; Martin, E.; Belmonte, M. M.; Benet-Buchholz, J.; Kleij, A. W. An Efficient Iron Catalyst for the Synthesis of Five- and Six-Membered Organic Carbonates under Mild Conditions Adv. Synth. Catal. 2012, 354, 469– 476 DOI: 10.1002/adsc.201100752
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An Efficient Iron Catalyst for the Synthesis of Five- and Six-Membered Organic Carbonates under Mild Conditions
Whiteoak, Christopher J.; Martin, Eddy; Belmonte, Marta Martinez; Benet-Buchholz, Jordi; Kleij, Arjan W.
Advanced Synthesis & Catalysis (2012), 354 (2-3), 469-476CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
An iron(III) amine triphenolate complex, [FeTPhOA]2, able to efficiently catalyze the cycloaddn. of carbon dioxide to a range of terminal epoxides under mild conditions, is described. In addn., it has also been found that the complex is able to catalyze the conversion with more sterically congested oxiranes and oxetanes which are generally considered challenging substrates to activate. Variation of the co-catalyst, required for ring-opening of the substrates, has also been examd. The results show that terminal epoxide substrates are converted more efficiently with an iodide co-catalyst, whereas more bulky oxirane substrates give better product yields in the presence of a bromide co-catalyst. The combined results demonstrate the broad applicability of these iron(III) complexes in this type of carbon dioxide fixation chem.
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Rintjema, J.; Guo, W.; Martin, E.; Escudero-Adán, E. C.; Kleij, A. W. Highly Chemoselective Catalytic Coupling of Substituted Oxetane and Carbon Dioxide Chem. - Eur. J. 2015, 21, 10754– 10762 DOI: 10.1002/chem.201501576
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Highly Chemoselective Catalytic Coupling of Substituted Oxetanes and Carbon Dioxide
Rintjema, Jeroen; Guo, Wusheng; Martin, Eddy; Escudero-Adan, Eduardo C.; Kleij, Arjan W.
Chemistry - A European Journal (2015), 21 (30), 10754-10762CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
An effective method for the synthesis of six-membered cyclic carbonates relying on the use of Al catalysis is described. The catalytic reactions can be carried out with excellent selectivity for the cyclic carbonate product tolerating various (functional) groups present in the 2- and 3-position(s) of the oxetane ring. The presented methodol. is the first general approach towards the formation of six-membered cyclic carbonates (6MCCs) through oxetane/CO2 coupling chem. Apart from a series of substituted six-membered cyclic carbonates e.g., I, also the unprecedented room-temp. coupling of oxetanes and CO2 is disclosed giving, depending on the structural features of the substrate, a variety of five- and six-membered heterocyclic products. A mechanistic rationale is presented for their formation and support for the intermediary presence of a carbonic acid deriv. is given. The presented functional carbonates may hold great promise as building blocks in org. synthesis and the development of new, biodegradable polymers.
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Guo, W.; Laserna, V.; Rintjema, J.; Kleij, A. W. Catalytic One-Pot Oxetane to Carbamate Conversions: Formal Synthesis of Drug Relevant Molecules Adv. Synth. Catal. 2016, 358, 1602– 1607 DOI: 10.1002/adsc.201500895
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Catalytic One-Pot Oxetane to Carbamate Conversions: Formal Synthesis of Drug Relevant Molecules
Guo, Wusheng; Laserna, Victor; Rintjema, Jeroen; Kleij, Arjan W.
Advanced Synthesis & Catalysis (2016), 358 (10), 1602-1607CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
Oxetanes are versatile building blocks in drug-related synthesis to induce property-modulating effects. Whereas related oxiranes are widely used in coupling chem. with CO2 to afford value-added commodity chems., oxetane/CO2 couplings remain extremely limited despite the recent advances in the synthesis of these four-membered heterocycles. Here we report an effective one-pot three-component reaction (3CR) strategy for the coupling of (substituted) oxetanes, amines, and CO2 to afford a variety of functionalized carbamates with excellent chemoselectivity and good yields. The process is mediated by an aluminum-based catalyst under relatively mild conditions and the developed catalytic methodol. can be applied to the formal synthesis of two pharmaceutically relevant carbamates with the 3CR being a key step.
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Charas, A.; Morgado, J. Oxetane-functionalized Conjugated Polymers in Organic (Opto)Electronic Devices Curr. Phys. Chem. 2012, 2, 241– 264 DOI: 10.2174/1877946811202030241
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Oxetane-functionalized conjugated polymers in organic (opto)electronic devices
Charas, Ana; Morgado, Jorge
Current Physical Chemistry (2012), 2 (3), 241-264CODEN: CPCUBU; ISSN:1877-9468. (Bentham Science Publishers Ltd.)
A review π-Conjugated polymers have found applications as active materials in a range of optoelectronic devices due to being intrinsically semiconducting, exhibiting switchable properties in the course of redox processes, and the possibility of being processed from soln. Current developments in mol. design have been extended to include switchable soly. by means of chem. crosslinking via polymn. of photo-reactive groups attached to the polymer backbone. Exploiting the cross-linkable ability of conjugated polymers has allowed extending applications to multilayered devices fabrication, as the cross-linked structure does not re-dissolve upon further deposition of solns., and also to patterning processes, at the sub-micrometric scale, based on photo-induced methods (photo-lithog.) or on phase-sepn. in spin cast polymer blends. Among the classes of cross-linkable conjugated polymers, those contg. oxetane units as the crosslinking moiety have been the most explored in terms of applications in optoelectronic devices. In this article, we review the recent progress in the field of oxetane-functionalized conjugated polymers, focusing on their mol. design to control electronic and processing properties and their most relevant applications in org. electronics.
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Crivello, J. V. Aryl Epoxides as Accelerators for the Photopolymerization of Oxetane Monomers J. Macromol. Sci., Part A: Pure Appl.Chem. 2015, 52, 336– 344 DOI: 10.1080/10601325.2015.1018803
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Aryl Epoxides as Accelerators for the Photopolymerization of Oxetane Monomers
Crivello, James V.
Journal of Macromolecular Science, Part A: Pure and Applied Chemistry (2015), 52 (5), 336-344CODEN: JSPCE6; ISSN:1060-1325. (Taylor & Francis, Inc.)
Epoxides bearing aryl groups function as "kick-starters" to markedly accelerate the photoinitiated cationic ring-opening polymn. of oxetane monomers. Thus, it has been obsd. that the inclusion of a small amt. of styrene oxide transforms a sluggishly polymg. 3-mono- or 3,3-disubstituted oxetane monomer into one that undergoes rapid, exothermic polymn. Mechanistic studies suggest that the activity of aryl epoxides as "kick-starters" is related to their ability to intercept photogenerated acids to form benzylic cations that rapidly initiate oxetane monomer polymn. by alkylation of the monomer.
30
Tsutsumi, H.; Suzuki, A. Cross-Linked Poly(oxetane) Matrix for Polymer Electrolyte Containing Lithium Ions Solid State Ionics 2014, 262, 761– 764 DOI: 10.1016/j.ssi.2013.09.049
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Pell, A. S.; Pilcher, G. Measurements of Heats of Combustion by Flame Calorimetry. Part 3. - Ethylene Oxide, Trimethylene Oxide, Tetrahydrofuran and Tetrahydropy Trans. Faraday Soc. 1965, 61, 71– 77 DOI: 10.1039/TF9656100071
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Eigenmann, H. K.; Golden, D. M.; Benson, S. W. Revised Group Additivity Parameters for the Enthalpies of Formation of Oxygen-Containing Organic Compounds J. Phys. Chem. 1973, 77, 1687– 1691 DOI: 10.1021/j100632a019
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Revised group additivity parameters for the enthalpies of formation of oxygen-containing organic compounds
Eigenmann, H. K.; Golden, D. M.; Benson, S. W.
Journal of Physical Chemistry (1973), 77 (13), 1687-91CODEN: JPCHAX; ISSN:0022-3654.
Data on ΔH f°, the std. enthalpies of formation in the gas phase for over 300 O-contg. compds. are critically examd. Internal consistencies within this set are scrutinized from the viewpoint of group additivity principles. New values for the contributions of groups to ΔHf°, as well as higher order corrections, are obtained from multilinear regression anal. of the data. For alcs. and ethers obsd. values and group additivity values agree to within ±1.0 kcal/mole, which is about the exptl. precision. The data on these classes are very self-consistent. Very nearly the same is true of aldehydes and ketones. Major discrepancies exist in the classes of acids and esters and a few key compds. deviate seriously from other members of their class.
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Chan, S. I.; Zinn, J.; Gwinn, W. D. Trimethylene Oxide. II. Structure, Vibration-Rotation Interaction, and Origin of Potential Function for Ring-Puckering Motion J. Chem. Phys. 1961, 34, 1319– 1329 DOI: 10.1063/1.1731739
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Trimethylene oxide. II. Structure, vibration-rotation interaction, and origin of potential function for ring-puckering motion
Chan, Sunney I.; Zinn, John; Gwinn, William D.
Journal of Chemical Physics (1961), 34 (), 1319-29CODEN: JCPSA6; ISSN:0021-9606.
cf. CA 55, 16149e. From the microwave spectra reported (loc. cit.), the structural parameters are calcd.; for trimethylene oxide (I), I-2,2,4,4-d4, I-O18, and I-3-d the effective moments of inertia of various vibrational states and rotational consts. are tabulated; from the latter, the parameters for the hypothetical planar I mol. are extrapolated. All bond angles and interat. distances of the ground, 1st excited, and planar states, and preferred structure are listed. The preferred parameters are: r(C-C) = 1.549 ± 0.003 A., r(C-O) = 1.449 ± 0.002 A., r(Cβ-Hβ) = 1.091 ± 0.002 A., r(Cβ-Hβ) = 1.100 ± 0.003 A., angle Cα-Cβ-Cα = 84°33' ± 1', angle Cα-O-Cα = 91°59' ± 7', angle Cβ-Cα-O = 91°44' ± 3', angle Hα-Cα-Hα = 110°18' ± 10', angle Hβ-Cβ-Hβ = 110°41' ± 3'. The α-methylene planes are slightly deflected towards the O, away from the bisectors of the angles Cβ-Cα-O. The actual angle of deflection is uncertain. By use of these parameters, models are constructed to calc. the vibration-rotation interaction due to the ring puckering vibration. The exptl. observed rotational const. variations are well reproduced if the out-of-plane bending motion is assumed to follow a curvilinear path without any stretching. The potential function detd. is interpreted in terms of force fields within the mol.
34
Luger, P.; Buschmann, J. Oxetane: The First X-Ray Analysis of a Nonsubstituted Four-Membered Ring J. Am. Chem. Soc. 1984, 106, 7118– 7121 DOI: 10.1021/ja00335a041
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Oxetane: the first x-ray analysis of a nonsubstituted four-membered ring
Luger, P.; Buschmann, J.
Journal of the American Chemical Society (1984), 106 (23), 7118-21CODEN: JACSAT; ISSN:0002-7863.
Crystallog. data, bond lengths and bond angles were detd. for oxetane by x-ray anal. at 90 and 140 K. The ring has exact Cs symmetry and is puckered with an angle of 10.7(1)° (90 K) and 8.7(2)° (140 K). The C-O bond length of 1.460(1) Å at 90 K is unusually large for a C-O single bond.
35
Gwinn, W. D. Information Pertaining to Molecular Structure, as Obtained from the Microwave Spectra of Molecules of the Asymmetric Rotor Type Discuss. Faraday Soc. 1955, 19, 43– 51 DOI: 10.1039/df9551900043
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Holan, G.; Kowala, C.; Wunderlich, J. A. X-Ray Determination of the Structure of a New Insecticide, 2,2-Di-(p-Ethoxyphenyl)-3,3-Dimethyloxetan J. Chem. Soc., Chem. Commun. 1973, 34– 34 DOI: 10.1039/c39730000034
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Searles, S.; Tamres, M. Hydrogen Bond Formation with Saturated Cyclic Ethers J. Am. Chem. Soc. 1951, 73, 3704– 3706 DOI: 10.1021/ja01152a041
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Brandon, M.; Tamres, O. P. M.; Searles, S., Jr. The Iodine Complexes of Some Saturated Cyclic Ethers.lS2 I. The Visible Region J. Am. Chem. Soc. 1960, 82, 2129– 2134 DOI: 10.1021/ja01494a010
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39
West, R.; Powell, D. L.; Lee, M. K. T.; Whatley, L. S. Hydrogen Bonding Studies. IX. The Thermodynamics of Hydrogen Bonding of Phenol to Ethers and Related Compounds J. Am. Chem. Soc. 1964, 86, 3227– 3229 DOI: 10.1021/ja01070a005
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Hydrogen bonding studies. IX. The thermodynamics of hydrogen bonding of phenol to ethers and related compounds
West, Robert; Powell, David L.; Lee, Margaret K. T.; Whatley, Linda S.
Journal of the American Chemical Society (1964), 86 (16), 3227-9CODEN: JACSAT; ISSN:0002-7863.
cf. CA 61, 2539c. The enthalpy and free energy of interaction of PhOH with 11 ethers, 2 sulfides, and 1 selenide have been detd. by a near-infrared spectrophotometric method. Chain branching α to the O atom increases the enthalpy of interaction, whereas aryl substitution decreases it. The cyclic ethers (CH2)3O, (CH2)4O, (CH2)5O, and 1,2-epoxyisobutane show about equal basicity toward PhOH. The dialkyl S and Se compds. are much weaker bases toward PhOH than analogous ethers. Implications of these findings are discussed.
40
Besseau, F.; Luçon, M.; Laurence, C.; Berthelot, M. Hydrogen-Bond Basicity pK_HB Scale of Aldehydes and Ketones J. Chem. Soc., Perkin Trans. 2 1998, 101– 108 DOI: 10.1039/a704427e
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Hydrogen-bond basicity pKHB scale of aldehydes and ketones
Besseau, Francois; Lucon, Maryvonne; Laurence, Christian; Berthelot, Michel
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1998), (1), 101-108CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)
The thermodn. hydrogen-bond basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-aldehyde or ketone complexes in CCl4 at 298 K) has been detd. for aldehydes, aliph. ketones, cycloalkanones, diketones and quinones, halogenated ketones, pyrones and related compds., acetophenones, benzophenones and various other conjugated ketones. The relationship between pKHB and a spectroscopic scale of basicity is obscured by the presence of two stereoisomeric complexes. In the R1COMe series the electronic and steric effects of the alkyl R1 almost cancel out, whereas steric effects prevail in R1COR2. Among alkyl substituents the 1-adamantyl is the most electron-donating. In cycloalkanones the basicity sequence with ring size is 4 < 11 ∼ 12 ∼ 15 < 5 < 6 < 7 < 8. Quant. structure-basicity relationships have been established in the arom. 3- and 4-XC6H4COMe and the aliph. XCOMe series. Intramol. hydrogen bonding causes a basicity decrease in acetylacetone. Hydrogen bonding sites are discussed.
41
Besseau, F.; Laurence, C.; Berthelot, M. Hydrogen-Bond Basicity of Esters, Lactones and Carbonates J. Chem. Soc., Perkin Trans. 2 1994, 485– 489 DOI: 10.1039/p29940000485
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Hydrogen-bond basicity of esters, lactones and carbonates
Besseau, Francois; Laurence, Christian; Berthelot, Michel
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1994), (3), 485-9CODEN: JCPKBH; ISSN:0300-9580.
A thermodn. hydrogen-bond-basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-base complexes in CCl4) has been detd. for esters, lactones and carbonates, and correlated to a spectroscopic basicity scale. In the esters R1CO2R2 the hydrogen-bond basicity is decreased by bulky alkyl R1 substituents (steric effect) but increased by branched and lengthened alkyl R2 substituents (electronic effects). Quant. structure-basicity relationships have been established in the XCO2Et (X varying from CF3 to Me2N) and XC6H4CO2Et (X varying from 4-NO2 to 4-Me2N) series. Vinylol. strongly increases hydrogen-bond basicity: Me2NCH:CHCO2Et is the most basic ester presently known. Cyclization increases the hydrogen-bond basicity of esters and carbonates.
42
Le Questel, J.-Y.; Laurence, C.; Lachkar, A.; Helbert, M.; Berthelot, M. Hydrogen-Bond Basicity of Secondary and Tertiary Amides, Carbamates, Ureas and Lactams J. Chem. Soc., Perkin Trans. 2 1992, 2091– 2094 DOI: 10.1039/p29920002091
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Hydrogen-bond basicity of secondary and tertiary amides, carbamates, ureas and lactams
Le Questel, Jean Yves; Laurence, Christian; Lachkar, Abdeljalil; Helbert, Maryvonne; Berthelot, Michel
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1992), (12), 2091-4CODEN: JCPKBH; ISSN:0300-9580.
A hydrogen-bond basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-base complexes in CCl4) has been measured for the title compds. The hydrogen-bonding site is the carbonyl group, even for the very hindered amide Me3CCON(C6H11)2. In the amides R1CONR2R3 the hydrogen-bond basicity is decreased more by bulky R1 substituents on the carbonyl carbon than by bulky R2 and R3 substituents on nitrogen. The field effect of X substituents operates more effectively on hydrogen-bond basicity than the resonance effect in the XCONMe2 series. The hydrogen-bond basicity is increased by six-membered cyclization.
43
Berthelot, M.; Besseau, F.; Laurence, C. The Hydrogen-Bond Basicity pK_HB Scale of Peroxides and Ethers Eur. J. Org. Chem. 1998, 1998, 925– 931 DOI: 10.1002/(SICI)1099-0690(199805)1998:5<925::AID-EJOC925>3.0.CO;2-F
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44
Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. Plant Antitumor Agents. VI. The Isolation and Structure of Taxol, a Novel Antileukemic and Antitumor Agent from Taxus Brevifolia J. Am. Chem. Soc. 1971, 93, 2325– 2327 DOI: 10.1021/ja00738a045
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Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia
Wani, Mansukhlal C.; Taylor, Harold Lawrence; Wall, Monroe E.; Coggon, Philip; McPhail, Andrew T.
Journal of the American Chemical Society (1971), 93 (9), 2325-7CODEN: JACSAT; ISSN:0002-7863.
Taxol (I), a complex ester with a taxane ring system exhibiting potent antileukemic and antitumor properties, was isolated from Taxus brevifolia (yew). BzNHCH(Ph)CH(OH)CO2Me and 5β,16-epoxy-1β,-2α,4α,7β,10β,13α-hexahydroxytax-11-en-9-one 4α-acetate 2α-benzoate are obtained by methanolysis of I. Based on chem. evidence, I is 5β,16-epoxy-1β,2α,4α,7β,10β,13α-hexahydroxytax-11-en-9-one 4α,10β-diacetate 2α-benzoate 13α-(3-benzamido-2-hydroxy-3-phenylpropionate).
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Gunatilaka, A. A. L.; Ramdayal, F. D.; Sarragiotto, M. H.; Kingston, D. G. I.; Sackett, D. L.; Hamel, E. Synthesis and Biological Evaluation of Novel Paclitaxel (Taxol) D-Ring Modified Analogues J. Org. Chem. 1999, 64, 2694– 2703 DOI: 10.1021/jo982095h
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Boge, T. C.; Hepperle, M.; Vander Velde, D. G.; Gunn, C. W.; Grunewald, G. L.; Georg, G. I. The Oxetane Conformational Lock of Paclitaxel: Structural Analysis of D-Secopaclitaxel Bioorg. Med. Chem. Lett. 1999, 9, 3041– 3046 DOI: 10.1016/S0960-894X(99)00521-1
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Marder-Karsenti, R.; Dubois, J.; Bricard, L.; Guénard, D.; Guéritte-Voegelein, F. Synthesis and Biological Evaluation of D-Ring-Modified Taxanes: 5(20)-Azadocetaxel Analogs J. Org. Chem. 1997, 62, 6631– 6637 DOI: 10.1021/jo9706842
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Wang, M.; Cornett, B.; Nettles, J.; Liotta, D. C.; Snyder, J. P. The Oxetane Ring in Taxol J. Org. Chem. 2000, 65, 1059– 1068 DOI: 10.1021/jo9916075
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The Oxetane Ring in Taxol
Wang, Minmin; Cornett, Ben; Nettles, Jim; Liotta, Dennis C.; Snyder, James P.
Journal of Organic Chemistry (2000), 65 (4), 1059-1068CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Numerous structure-activity studies combining synthesis and bioassay have been performed for the anti-cancer drug taxol. The four-membered D-ring, an oxetane, is one of four structural features regarded to be essential for biol. activity. This proposition is examd. by application of a taxol-epothilone minireceptor, Ki estn. for microtubule binding and docking of taxol analogs into a model of the taxol-tubulin complex. The two characteristics considered responsible for oxetane function were examd.: (1) rigidification of the tetracyclic taxol core to provide an appropriate framework for presenting the C-2, C-4, C-13 side chains to the microtubule protein and (2) service as a hydrogen-bond acceptor. An energy decompn. anal. for a series of taxol analogs demonstrated the oxetane ring clearly operates by both mechanisms. A broader anal. of four-membered ring contg. compds., C- and D-seco derivs., and structures with no oxetane equiv. underscores that the four-membered ring is not necessary for taxol analog bioactivity. Other functional groups and ligand-protein binding characteristics are fully capable of delivering taxol biobehavior as effectively as the oxetane D-ring. This information may contribute to the design and development of novel anticancer drugs.
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Wang, S.-R.; Yang, C.-G.; Sánchez-Murcia, P. A.; Snyder, J. P.; Yan, N.; Sáez-Calvo, G.; Díaz, J. F.; Gago, F.; Fang, W.-S. Restoration of Microtubule Interaction and Cytotoxicity in D-Seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-Allyloxy Groups Org. Lett. 2015, 17, 6098– 6101 DOI: 10.1021/acs.orglett.5b03119
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Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups
Wang, Shao-Rong; Yang, Chun-Gang; Sanchez-Murcia, Pedro A.; Snyder, James P.; Yan, Ning; Saez-Calvo, Gonzalo; Diaz, Jose Fernando; Gago, Federico; Fang, Wei-Shuo
Organic Letters (2015), 17 (24), 6098-6101CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepd. from paclitaxel. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane (I) is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than paclitaxel on tubulin polymn. promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and mol. modeling studies. From these results, the authors draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.
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Hefner, J.; Rubenstein, S. M.; Ketchum, R. E.; Gibson, D. M.; Williams, R. M.; Croteau, R. Cytochrome P450-Catalyzed Hydroxylation of Taxa-4(5),11(12)-diene to Taxa-4(20),11(12)-dien-5α-ol: The First Oxygenation Step in Taxol Biosynthesis Chem. Biol. 1996, 3, 479– 489 DOI: 10.1016/S1074-5521(96)90096-4
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Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5α-ol: the first oxygenation step in taxol biosynthesis
Hefner, Jerry; Rubenstein, Steven M.; Ketchum, Raymond E. B.; Gibson, Donna M.; Williams, Robert M.; Croteau, Rodney
Chemistry & Biology (1996), 3 (6), 479-489CODEN: CBOLE2; ISSN:1074-5521. (Current Biology)
The biosynthesis of taxol involves the cyclization of the common isoprenoid intermediate geranylgeranyl diphosphate to taxa-4(5),11(12)-diene followed by extensive, largely oxidative, modification of this diterpene olefin. We set out to define the first oxygenation step in taxol biosynthesis. Microsomal enzymes from Taxus stem and cultured cells were used to define the first hydroxylation of taxadiene. We confirmed the structure of the reaction product (taxa-4(20),11(12)-dien-5α-ol) by synthesizing this compd. The responsible biol. catalyst was characterized as a cytochrome P 450 (heme thiolate protein). In vivo studies confirmed that taxadienol is a biosynthetic intermediate and indicated that the hydroxylation step that produces this product is slow relative to subsequent metabolic transformations. The structure of the first oxygenated intermediate on the taxol pathway establishes that the hydroxylation reaction proceeds with an unusual double bond migration that limits the mechanistic possibilities for subsequent elaboration of the oxetane moiety of taxol. The reaction is catalyzed by a cytochrome P 450, suggesting that the 7 remaining oxygenation steps in taxol biosynthesis may involve similar catalysts. Because the first oxygenation step is slow relative to subsequent metabolic transformations, it may be possible to speed taxol biosynthesis by isolating and manipulating the gene for the taxadiene-5-hydroxylase that catalyzes this reaction.
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Guéritte-Voegelein, F.; Guénard, D.; Potier, P. Taxol and Derivatives: A Biogenetic Hypothesis J. Nat. Prod. 1987, 50, 9– 18 DOI: 10.1021/np50049a002
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Taxol and derivatives: a biogenetic hypothesis
Gueritte-Voegelein, Francoise; Guenard, Daniel; Potier, Pierre
Journal of Natural Products (1987), 50 (1), 9-18CODEN: JNPRDF; ISSN:0163-3864.
A review with 70 refs. on structure differences of compds. isolated from Taxus species and their relation to a biogenic approach and synthesis of taxol (I).
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Swindell, C. S.; Britcher, S. F. Construction of the Taxane C-Ring Epoxy Alcohol Moiety and Examination of its Possible Involvement in the Biogenesis of the Taxane 3-Oxetanol Structure J. Org. Chem. 1986, 51, 793– 797 DOI: 10.1021/jo00356a005
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Construction of the taxane C-ring epoxy alcohol moiety and examination of its possible involvement in the biogenesis of the taxane 3-oxetanol structure
Swindell, Charles S.; Britcher, Susan F.
Journal of Organic Chemistry (1986), 51 (6), 793-7CODEN: JOCEAH; ISSN:0022-3263.
A stereospecific synthesis of a model compd. I (R = H), contg. the 2,3-epoxy alc. moiety present in the C-ring of several taxane diterpenes, was accomplished. Thus, epoxide II was converted to allylic alc. III, which upon epoxidn. gave epoxide IV, followed by treatment with hydroxide to give I (R = H). Methanesulfonate I (R = MeSO2) gave ketone V upon solvolysis in aq. MeCN. Two possible mechanisms for this transformation are provided. This last expt. was designed to evaluate a described suggestion regarding the biogenesis of the taxane C-ring 3-oxetanol moiety.
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Willenbring, D.; Tantillo, D. J. Mechanistic Possibilities for Oxetane Formation in the Biosynthesis of Taxol’s D Ring Russ. J. Gen. Chem. 2008, 78, 723– 731 DOI: 10.1134/S1070363208040336
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Mechanistic possibilities for oxetane formation in the biosynthesis of Taxol's D ring
Willenbring, Dan; Tantillo, Dean J.
Russian Journal of General Chemistry (2008), 78 (4), 723-731CODEN: RJGCEK; ISSN:1070-3632. (Pleiades Publishing, Ltd.)
Three mechanistic possibilities for the formation of the oxetane (D ring) of Taxol were examd. at various levels of theory [B3LYP/6-31+G(d,p), mPW1PW91/6-31+G(d,p), and MP2/6-31+G(d,p)] including one mechanism involving an unusual oxabicyclobutonium ion intermediate. The mechanisms examd. differ considerably in terms of their predicted inherent activation barriers, and the requirements for acceleration of each by an enzyme active site are outlined. Our calcns. provide an important starting point for future studies in this area. Also examd. were previously published calcns. on simple oxabicyclobutonium ions, as well as the all-carbon analog of the pathway involving the oxabicyclobutonium ion.
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Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii, A.; Takita, T. Oxetanocin, a Novel Nucleoside from Bacteria J. Antibiot. 1986, 39, 1623– 1625 DOI: 10.7164/antibiotics.39.1623
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Oxetanocin, a novel nucleoside from bacteria
Shimada, Nobuyoshi; Hasegawa, Shigeru; Harada, Takashi; Tomisawa, Takayuki; Fujii, Akio; Takita, Tomohisa
Journal of Antibiotics (1986), 39 (11), 1623-5CODEN: JANTAJ; ISSN:0021-8820.
The prodn., isolation, and chem. and biol. properties of oxetanocin (9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanyl]adenine) from Bacillus megaterium are reported. Oxetanocin at the levels tested showed activity against herpes simplex virus-II and cytotoxicity against Vero cells, but no activity against vesicular stomatitis virus. It inhibited growth of HeLa cells in vitro and showed strong antibacterial activity against Staphylococcus aureus and several Bacillus species. Adenine and adenosine were antagonistic toward the antibacterial activity of oxetanocin; guanosine and the inosine showed a weak antagonistic effect. I.v. infection of oxetanocin to mice showed no toxicity.
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Omura, S.; Murata, M.; Imamura, N.; Iwai, Y.; Tanaka, H.; Furusaki, A.; Matsumoto, H. Oxetin, a New Antimetabolite from an Actinomycete. Fermentation, Isolation, Structure and Biological Activity J. Antibiot. 1984, 37, 1324– 1332 DOI: 10.7164/antibiotics.37.1324
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Oxetin, a new antimetabolite from an actinomycete. Fermentation, isolation, structure and biological activity
Omura, Satoshi; Murata, Masatsune; Imamura, Nobutaka; Iwai, Yuzuru; Tanaka, Haruo; Furusaki, Akio; Matsumoto, Takeshi
Journal of Antibiotics (1984), 37 (11), 1324-32CODEN: JANTAJ; ISSN:0021-8820.
A new amino acid-antimetabolite, oxetin (I), was isolated from a fermn. broth of a Streptomyces sp. OM-2317, a soil isolate. The chem. structure was elucidated as (2R,3S)-3-amino-2-oxetane carboxylic acid by anal. of the spectral data and by x-ray diffraction methods. I is the first natural product possessing an oxetane ring. Certain microorganisms were inhibited by I only when cultivated in minimal media. The inhibitory action was reversed by several amino acids such as L-isoleucine, L-methionine, L-valine, and L-glutamine. It also exhibited herbicidal activity and inhibited glutamine synthetase from spinach leaves.
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Han, Q.; Zhang, J.; Lu, Y.; Wu, Y.; Zheng, Q.; Sun, H. A Novel Cytotoxic Oxetane ent-Kauranoid from Isodon Japonicus Planta Med. 2004, 70, 581– 584 DOI: 10.1055/s-2004-827165
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A novel cytotoxic oxetane ent-kauranoid from Isodon japonicus
Han, Quanbin; Zhang, Jixia; Lu, Yang; Wu, Yunshan; Zheng, Qitai; Sun, Handong
Planta Medica (2004), 70 (6), 581-584CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
A novel 11,20:1,20-diepoxy-ent-kaurane diterpenoid, maoyecrystal I (I), was isolated from Isodon japonicus, and its structure was elucidated by spectroscopic methods and comparison with another new ent-kauranoid, rubescensin W (II) from Isodon rubescens var. taihangensis. The structure of II was detd. by single crystal x-ray diffraction anal. A bioassay of their cytotoxicity against K562 cells showed that the oxetane group of I might be a bioactive moiety.
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Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Burgess, J. P.; Riswan, S.; Setyowati, F. M.; Saribi, A. M.; Soejarto, D. D. A Hexacyclic ent-Trachylobane Diterpenoid Possessing an Oxetane Ring from Mitrephora Glabra Org. Lett. 2005, 7, 5709– 5712 DOI: 10.1021/ol052498l
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A Hexacyclic ent-Trachylobane Diterpenoid Possessing an Oxetane Ring from Mitrephora glabra
Li, Chen; Lee, Dongho; Graf, Tyler N.; Phifer, Sharnelle S.; Nakanishi, Yuka; Burgess, Jason P.; Riswan, Soedarsono; Setyowati, Fransisca M.; Saribi, Achmad M.; Soejarto, Djaja D.; Farnsworth, Norman R.; Falkinham, Joseph O., III; Kroll, David J.; Kinghorn, A. Douglas; Wani, Mansukh C.; Oberlies, Nicholas H.
Organic Letters (2005), 7 (25), 5709-5712CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Three new ent-trachylobane diterpenoids (I-III) were isolated and structures elucidated from Mitrephora glabra Scheff. (Annonaceae). Mitrephorone A possesses a hexacyclic ring system with adjacent ketone moieties and an oxetane ring, both of which are unprecedented among trachylobanes. All compds. were evaluated for cytotoxicity against a panel of cancer cells, where 1 displayed the most potent and broadest activity, and against a battery of antimicrobial assays, where all compds. were approx. equipotent.
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Hamberg, M.; Svensson, J.; Samuelsson, B. Thromboxanes: A New Group of Biologically Active Compounds Derived from Prostaglandin Endoperoxides Proc. Natl. Acad. Sci. U. S. A. 1975, 72, 2994– 2998 DOI: 10.1073/pnas.72.8.2994
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Thromboxanes. New group of biologically active compounds derived from prostaglandin endoperoxides
Hamberg, Mats; Svensson, Jan; Samuelsson, Bengt
Proceedings of the National Academy of Sciences of the United States of America (1975), 72 (8), 2994-8CODEN: PNASA6; ISSN:0027-8424.
An unstable (t1/2 at 37° = 32 sec) intermediate, thromboxane A2, was detected in the conversion of prostaglandin G2 into thromboxane B2 in platelets. The intermediate was trapped by addn. of MeOH, EtOH, or NaN3 to suspensions of washed human platelets incubated for 30 sec with arachidonic acid or prostaglandin G2. The structures of the resulting derivs. demonstrated that the intermediate possessed an oxane ring as in thromboxane B2 but lacked its hemiacetal OH group. Addnl. expts. using 18O or arachidonic acid 2H8 in the formation of thromboxane B2 and CH3O2H for the trapping of thromboxane A2, together with information on the t1/2 of the intermediate, indicated the presence of an oxetane structure in thromboxane A2. Incubation of arachidonic acid or prostaglandin G2 with washed platelets led to the formation of an unstable factor that induced irreversible platelet aggregation and caused release of serotonin-14C from platelets that were incubated with labeled serotonin. The properties and the mode of formation of this factor indicated that it was identical with thromboxane A2. Furthermore, evidence was presented that the more unstable and major component of rabbit aorta contracting substance formed in platelets and guinea pig lung is also thromboxane A2.
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Huang, J.; Yokoyama, R.; Yang, C.; Fukuyama, Y. Merrilactone A, a Novel Neurotrophic Sesquiterpene Dilactone from Illicium Merrillianum Tetrahedron Lett. 2000, 41, 6111– 6114 DOI: 10.1016/S0040-4039(00)01023-6
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Merrilactone A, a novel neurotrophic sesquiterpene dilactone from Illicium merrillianum
Huang, J.-m.; Yokoyama, R.; Yang, C.-s.; Fukuyama, Y.
Tetrahedron Letters (2000), 41 (32), 6111-6114CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
Merrilactone A (I), isolated from the pericarps of Illicium merrillianum, shows an intriguing neurotrophic activity in the cultures of fetal rat cortical neurons. Its structure has been elucidated to be a unique sesquiterpene bearing two γ-lactones and an oxetane ring by extensive analyses of spectral data and then confirmed by X-ray crystallog. anal. Further, the abs. configuration has been established by the modified Mosher's method.
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Pullaiah, K. C.; Surapaneni, R. K.; Rao, C. B.; Albizati, K. F.; Sullivan, B. W.; Faulkner, D. J.; He, C. H.; Clardy, J. Dictyoxetane, a Novel Diterpene from the Brown Alga Dictyota Dichotoma from the Indian Ocean J. Org. Chem. 1985, 50, 3665– 3666 DOI: 10.1021/jo00219a057
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Dictyoxetane, a novel diterpene from the brown alga Dictyota dichotoma from the Indian Ocean
Pullaiah, K. C.; Surapaneni, R. K.; Rao, C. Bheemasankara; Albizati, Kim F.; Sullivan, Brian W.; Faulkner, D. John; He, Cun Heng; Clardy, Jon
Journal of Organic Chemistry (1985), 50 (19), 3665-6CODEN: JOCEAH; ISSN:0022-3263.
Dictyoxetane (I), isolated from an Indian Ocean specimen of the brown alga D. dichotoma, is the 1st example of a new tricyclic diterpene C skeleton. The structure of I was detd. by x-ray anal.
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Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. Synthesis of a 2,7-Dioxatricyclo[4.2.1.0 3,8 ]nonane: A Model Study for Possible Application in a Synthesis of Dictyoxetane J. Org. Chem. 1996, 61, 9135– 9145 DOI: 10.1021/jo961680k
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Loh, J.; Carlson, R. W.; York, W. S.; Stacey, G. Bradyoxetin, a Unique Chemical Signal Involved in Symbiotic Gene Regulation Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14446– 14451 DOI: 10.1073/pnas.222336799
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Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Oxetanes as Promising Modules in Drug Discovery Angew. Chem., Int. Ed. 2006, 45, 7736– 7739 DOI: 10.1002/anie.200602343
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Oxetanes as promising modules in drug discovery
Wuitschik, Georg; Rogers-Evans, Mark; Mueller, Klaus; Fischer, Holger; Wagner, Bjoern; Schuler, Frnaz; Polonnchuk, Liudmila; Carreira, Erick M.
Angewandte Chemie, International Edition (2006), 45 (46), 7736-7739CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Introduction of an oxetane ring results in remarkably improved physico- and biochem. properties of the underlying scaffold. The oxetane ring confers enhanced soly., reduces the metabolic degrdn., lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
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Wuitschik, G.Oxetanes in Drug Discovery; Ph.D. Thesis, ETH Zurich, 2008.
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Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. Oxetanes in Drug Discovery: Structural and Synthetic Insights J. Med. Chem. 2010, 53, 3227– 3246 DOI: 10.1021/jm9018788
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Oxetanes in Drug Discovery: Structural and Synthetic Insights
Wuitschik, Georg; Carreira, Erick M.; Wagner, Bjorn; Fischer, Holger; Parrilla, Isabelle; Schuler, Franz; Rogers-Evans, Mark; Muller, Klaus
Journal of Medicinal Chemistry (2010), 53 (8), 3227-3246CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The use of oxetanes as replacements for gem-di-Me or carbonyl groups and their effects on the aq. soly., lipophilicity, metabolic stability, and conformation for various compds. are studied; methods for the prepn. of a variety of substituted oxetanes are given. The magnitude of changes in properties and in metabolic stability with oxetane substitution depends on the structural context; for example, substitution of a gem-di-Me group with an oxetane, aq. soly. may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degrdn. in most cases. Incorporation of an oxetane into an aliph. chain increases in some cases the preference for synclinal conformations rather than antiplanar conformations of the chain. Spirocyclic oxetanes such as an oxazaspiroheptane resemble commonly used fragments in drug discovery, such as morpholines, and in some cases increase aq. soly. more effectively than morpholines. An improved chemoselective oxidn. of 3-oxetanol to 3-oxetanone is disclosed; olefination of 3-oxetanone by a variety of methods yields alkylideneoxetanes I [R = (EtO)2P(:O), OHC, O2N, EtO2C, NC, PhO2S, MeCO, 1-(4-chlorophenyl)-1-cyclobutanecarbonyl]. I (R = EtO2C, OHC, O2N) undergo addn. reactions with nucleophiles such as amines, carbonyl compds., and arylboronic acids to give oxetanes such as II. The crystal structures of a variety of oxetanes are detd.
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Waring, M. J. Lipophilicity in Drug Discovery Expert Opin. Drug Discovery 2010, 5, 235– 248 DOI: 10.1517/17460441003605098
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Lipophilicity in drug discovery
Waring, Michael J.
Expert Opinion on Drug Discovery (2010), 5 (3), 235-248CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)
A review. Importance of the field: The role of lipophilicity in detg. the overall quality of candidate drug mols. is of paramount importance. Recent developments suggest that, as well as detg. pre-clin. ADMET (absorption, distribution, metab., elimination and toxicol.) properties, compds. of optimal lipophilicity might have increased chances of success in development. Areas covered in this review: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compd. Quality' with lipophilicity. What the reader will gain: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region. Take home message: The review of the data shows that this optimal space is defined by a narrow range of logD between ∼ 1 and 3. Some of the implications of this for medicinal chem. optimization are discussed.
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Moore, J. C.; Battino, R.; Rettich, T. R.; Handa, Y. P.; Wilhelm, E. Partial Molar Volumes of “Gases” at Infinite Dilution in Water at 298.15 K J. Chem. Eng. Data 1982, 27, 22– 24 DOI: 10.1021/je00027a005
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Edward, J. T.; Farrell, P. G.; Shahidi, F. Partial Molar Volumes of Organic Compounds in Water. Part 1. – Ethers, Ketones, Esters and Alcohols J. Chem. Soc., Faraday Trans. 1 1977, 73, 705– 714 DOI: 10.1039/f19777300705
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Partial molar volumes of organic compounds in water. Part 1. Ethers, ketones, esters, and alcohols
Edward, John T.; Farrell, Patrick G.; Shahidi, Fereidoon
Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases (1977), 73 (5), 705-14CODEN: JCFTAR; ISSN:0300-9599.
The partial molar vols. of 81 ethers, ketones, esters, and alcs. in H2O at 25.0° were detd. and related to their van der Waals vols. by 2 equations, for spherical and cylindrical mols., resp. Allowance was made for the void vol. assocd. with each mol. Because of H bonding to H2O, the calcd. vols. must be reduced by a const. amt. for each CO or OH group present, but not for the O atoms of the ethers. For diols, the void vol. per addnl. CH2 group remains const. for straight-chain mols. (i.e., cylinders) but decreases with the no. of C atoms for spherical mols., as is predicted.
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Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F. Spirocyclic Oxetanes: Synthesis and Properties Angew. Chem., Int. Ed. 2008, 47, 4512– 4515 DOI: 10.1002/anie.200800450
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Spirocyclic oxetanes: synthesis and properties
Wuitschik, Georg; Rogers-Evans, Mark; Buckl, Andreas; Bernasconi, Maurizio; Marki, Moritz; Godel, Thierry; Fischer, Holger; Wagner, Bjorn; Parrilla, Isabelle; Schuler, Franz; Schneider, Josef; Alker, Andre; Schweizer, W. Bernd; Muller, Klaus; Carreira, Erick M.
Angewandte Chemie, International Edition (2008), 47 (24), 4512-4515CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Spirocyclic oxetanes are described as analogs of morpholine and also as topol. siblings of their carbonyl counterparts. They are particularly promising in terms of both their physicochem. properties and the ease with which they can be grafted onto mol. structures. The data collected highlight oxetanes as both the hydrophilic sister of a gem-di-Me unit and the carbonyl group's lipophilic brother.
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Fujishima, T.; Nozaki, T.; Suenaga, T. Design and Synthesis of Novel 1,25-Dihydroxyvitamin D3 Analogues Having a Spiro-Oxetane Fused at the C2 Position in the A-Ring Bioorg. Med. Chem. 2013, 21, 5209– 5217 DOI: 10.1016/j.bmc.2013.06.032
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Fujishima, T.; Suenaga, T.; Nozaki, T. Concise Synthesis and Characterization of Novel Seco-Steroids Bearing a Spiro-Oxetane instead of a Metabolically Labile C3-Hydroxy Group Tetrahedron Lett. 2014, 55, 3805– 3808 DOI: 10.1016/j.tetlet.2014.05.060
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Burkhard, J.; Carreira, E. M. 2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions Org. Lett. 2008, 10, 3525– 3526 DOI: 10.1021/ol801293f
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2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions
Burkhard, Johannes; Carreira, Erick M.
Organic Letters (2008), 10 (16), 3525-3526CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc-N'-aryl-2,6-diazaspiro[3.3]heptanes.
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Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Müller, K.; Carreira, E. M. Synthesis of Azaspirocycles and Their Evaluation in Drug Discovery Angew. Chem., Int. Ed. 2010, 49, 3524– 3527 DOI: 10.1002/anie.200907108
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Synthesis of Azaspirocycles and their Evaluation in Drug Discovery
Burkhard, Johannes A.; Wagner, Bjoern; Fischer, Holger; Schuler, Franz; Mueller, Klaus; Carreira, Erick M.
Angewandte Chemie, International Edition (2010), 49 (20), 3524-3527, S3524/1-S3524/60CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Readily synthesized heteroatom-substituted spiro[3.3]heptanes generally show higher aq. soly. than their cyclohexane analogs, and show a trend towards higher metabolic stability. The novel framework can be mounted onto scaffolds of druglike structures, such as fluoroquinolones, to afford active compds. with similar or even improved metabolic stability.
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Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks Org. Lett. 2012, 14, 66– 69 DOI: 10.1021/ol2028459
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Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks
Burkhard, Johannes A.; Guerot, Carine; Knust, Henner; Carreira, Erick M.
Organic Letters (2012), 14 (1), 66-69CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The prepn. of versatile azaspiro[3.3]heptanes, e.g., I, carrying multiple exit vectors, is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.
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Burkhard, J. A.; Guérot, C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Synthesis and Structural Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks for Medicinal Chemistry Org. Lett. 2010, 12, 1944– 1947 DOI: 10.1021/ol1003302
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Synthesis and Structural Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks for Medicinal Chemistry
Burkhard, Johannes A.; Guerot, Carine; Knust, Henner; Rogers-Evans, Mark; Carreira, Erick M.
Organic Letters (2010), 12 (9), 1944-1947CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes, such as 1,6-diazaspiro[3.3]heptanes, is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallog. structures.
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Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery Org. Lett. 2011, 13, 6134– 6136 DOI: 10.1021/ol2025313
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Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery
Li, Dong-Bo; Rogers-Evans, Mark; Carreira, Erick M.
Organic Letters (2011), 13 (22), 6134-6136CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Step-economic and scalable syntheses of novel thiaazaspiro[3.4]octanes I (X = S, SO2, Y = CH2; X = CH2, Y = S, SO2; Z = CO, CHOH, CHNH2, CHCO2H, etc.) are reported. These spirocycles and some related intermediates can serve as uncharted multifunctional modules for drug discovery chem.
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Guérot, C.; Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Synthesis of Novel Angular Spirocyclic Azetidines Org. Lett. 2011, 13, 780– 783 DOI: 10.1021/ol103050c
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Synthesis of Novel Angular Spirocyclic Azetidines
Guerot, Carine; Tchitchanov, Boris H.; Knust, Henner; Carreira, Erick M.
Organic Letters (2011), 13 (4), 780-783CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The syntheses of a variety of novel angular azaspiro[3.3]heptanes, e.g., I, are reported. Gem-Difluoro and gem-di-Me variants of the angular 1,6-diazaspiro[3.3]heptane module were prepd. in high yields using efficient sequences. Addnl., a practical one-pot synthesis of 5-oxo-2-azaspiro[3.3]heptanes and subsequent conversions into functionalized derivs. are described. The methods reported are amenable to the synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale.
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Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes Org. Lett. 2013, 15, 4766– 4769 DOI: 10.1021/ol402127b
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Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes
Li, Dong Bo; Rogers-Evans, Mark; Carreira, Erick M.
Organic Letters (2013), 15 (18), 4766-4769CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
New classes of thia/oxa-azaspiro[3.4]octanes are synthesized through the implementation of robust and step-economic routes. The targeted spirocycles have been designed to act as novel, multifunctional, and structurally diverse modules for drug discovery. Furthermore, enantioselective approaches to the spirocycles are reported.
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Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly, M. G. Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl–Aryl Suzuki Coupling Org. Lett. 2008, 10, 3259– 3262 DOI: 10.1021/ol8011327
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Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl-Aryl Suzuki Coupling
Duncton, Matthew A. J.; Estiarte, M. Angels; Tan, Darlene; Kaub, Carl; O'Mahony, Donogh J. R.; Johnson, Russell J.; Cox, Matthew; Edwards, William T.; Wan, Min; Kincaid, John; Kelly, Michael G.
Organic Letters (2008), 10 (15), 3259-3262CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chem. An efficient approach to installing these two modules into arom. systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.
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Burkhard, J. A.; Wuitschik, G.; Plancher, J.-M.; Rogers-Evans, M.; Carreira, E. M. Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide Org. Lett. 2013, 15, 4312– 4315 DOI: 10.1021/ol401705a
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Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide
Burkhard, Johannes A.; Wuitschik, Georg; Plancher, Jean-Marc; Rogers-Evans, Mark; Carreira, Erick M.
Organic Letters (2013), 15 (17), 4312-4315CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Oxetanes are used in drug discovery to enable physicochem. and metabolic property enhancement for the structures to which they are grafted. An imide C=O to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochem. and in vitro properties of the parent drugs, with an important exception: oxetane analog I displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metab., blocking in vivo racemization, and potentially altering teratogenicity is appealing.
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Dowling, J. E.; Alimzhanov, M.; Bao, L.; Block, M. H.; Chuaqui, C.; Cooke, E. L.; Denz, C. R.; Hird, A.; Huang, S.; Larsen, N. A. Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo ACS Med. Chem. Lett. 2013, 4, 800– 805 DOI: 10.1021/ml400197u
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Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo
Dowling, James E.; Alimzhanov, Marat; Bao, Larry; Block, Michael H.; Chuaqui, Claudio; Cooke, Emma L.; Denz, Christopher R.; Hird, Alex; Huang, Shan; Larsen, Nicholas A.; Peng, Bo; Pontz, Timothy W.; Rivard-Costa, Caroline; Saeh, Jamal Carlos; Thakur, Kumar; Ye, Qing; Zhang, Tao; Lyne, Paul D.
ACS Medicinal Chemistry Letters (2013), 4 (8), 800-805CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors, e.g., I, of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched mol. pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKTS129, a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
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Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.; Won, A.; Subramanyam, C.; Efremov, I. V.; O’Donnell, C. J. Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors J. Med. Chem. 2011, 54, 7772– 7783 DOI: 10.1021/jm200893p
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Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors
Stepan, Antonia F.; Karki, Kapil; McDonald, W. Scott; Dorff, Peter H.; Dutra, Jason K.; DiRico, Kenneth J.; Won, Annie; Subramanyam, Chakrapani; Efremov, Ivan V.; O'Donnell, Christopher J.; Nolan, Charles E.; Becker, Stacey L.; Pustilnik, Leslie R.; Sneed, Blossom; Sun, Hao; Lu, Yasong; Robshaw, Ashley E.; Riddell, David; O'Sullivan, Theresa J.; Sibley, Evelyn; Capetta, Steven; Atchison, Kevin; Hallgren, Andrew J.; Miller, Emily; Wood, Anthony; Obach, R. Scott
Journal of Medicinal Chemistry (2011), 54 (22), 7772-7783CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A metab.-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analog 6 suffered from extensive oxidn. on the cycloalkyl motif by cytochrome P 450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and THF analogs, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further redn. in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metab., relative to its 2-substituted isomer. The slower rates of metab. with 3-substituted cyclic ethers most likely originate from redns. in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacol. studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in drug likeness of mols. through the use of the oxetane motif.
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Stepan, A. F.; Kauffman, G. W.; Keefer, C. E.; Verhoest, P. R.; Edwards, M. Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter “Lipophilic Metabolism Efficiency” (LipMetE) and a Matched Molecular Pairs Analysis J. Med. Chem. 2013, 56, 6985– 6990 DOI: 10.1021/jm4008642
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Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter "Lipophilic Metabolism Efficiency" (LipMetE) and a Matched Molecular Pairs Analysis
Stepan, Antonia F.; Kauffman, Gregory W.; Keefer, Christopher E.; Verhoest, Patrick R.; Edwards, Martin
Journal of Medicinal Chemistry (2013), 56 (17), 6985-6990CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We have obsd. previously that modification of ring size and substitution pattern may be used as a strategy to mitigate the metabolic instability of cycloalkyl ethers. In this article, we introduce a medicinal chem. design parameter named "lipophilic metab. efficiency" (LipMetE) that indicates that these changes in metabolic stability can be largely ascribed to changes in lipophilicity. Our matched mol. pair anal. also indicates that this finding is a general phenomenon, widely obsd. across different chemotypes. It is our hope that both the LipMetE design parameter and the results from our pairwise anal. will be useful tools for medicinal chemists.
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Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-Guided Drug Design MedChemComm 2013, 4, 631– 652 DOI: 10.1039/c2md20317k
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Metabolism-guided drug design
Stepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.
MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
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Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A. Studies on the Synthesis, Stability and Conformation of 2-Sulfonyl-Oxetane Fragments Org. Biomol. Chem. 2015, 13, 5265– 5272 DOI: 10.1039/C5OB00549C
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Studies on the synthesis, stability and conformation of 2-sulfonyl-oxetane fragments
Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A.
Organic & Biomolecular Chemistry (2015), 13 (18), 5265-5272CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
2-(Arylsulfonyl)oxetanes, I [R is H, Me-4, Cl-4, Me-2, Cl-2, Cl-3, F-4, Br-4, CF3-4, OMe-4] and II, have been prepd. as new structural motifs of interest for medicinal chem. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compds. The oxetane ring is constructed through an efficient C-C bond forming cyclization which allows the incorporation of a wide range of aryl-sulfonyl groups. Furthermore, biaryl-contg. compds. can be accessed through Suzuki-Miyaura coupling from halogenated derivs. With a no. of oxetane contg. fragment compds. available, their pH stability was assessed, indicating good half-life values for mono-substituted aryl sulfonyl oxetanes across the pH range (1 to 10). Soly. and metabolic stability data is also reported. Finally, the conformation of the fragments is assessed computationally, providing an indication of possible binding orientations.
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Lucas, S. D.; Iding, H.; Alker, A.; Wessel, H. P.; Rauter, A. P. Oxetane δ-Amino Acids: Chemoenzymatic Synthesis of 2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic Acid J. Carbohydr. Chem. 2006, 25, 187– 196 DOI: 10.1080/07328300600732485
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Oxetane δ-amino acids: chemoenzymatic synthesis of 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid
Lucas, Susana Dias; Iding, Hans; Alker, Andre; Wessel, Hans Peter; Rauter, Amelia Pilar
Journal of Carbohydrate Chemistry (2006), 25 (2-3), 187-196CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
Starting from 1,2-O-isopropylidene-D-xylose, Me 2,4-anhydro-3,5-di-O-benzyl-D-lyxonate (4) was synthesized. Debenzylation and transformation of the primary hydroxyl group yielded Me 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonate (9). While transesterification of 4 under basic reaction conditions was straightforward, an analogous reaction with 9 was not successful. After screening of several lipases, the enzymic transesterification of 9 was achieved with lipase L2 from Candida antarctica to furnish the title compd. 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid in excellent yield. The stereochem. at the oxetane ring was proven by an x-ray structure of the intermediate Me 2,4-anhydro-5-azido-D-lyxonate.
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Lucas, S. D.; Rauter, A. P.; Wessel, H. P. Synthesis of 3-Methoxyoxetane δ-Amino Acids with D-Lyxo, D-Ribo, and D-Arabino Configurations J. Carbohydr. Chem. 2008, 27, 172– 187 DOI: 10.1080/07328300802061717
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Synthesis of 3-methoxyoxetane δ-amino acids with D-lyxo, D-ribo, and D-arabino configurations
Lucas, Susana Dias; Rauter, Amelia Pilar; Wessel, Hans Peter
Journal of Carbohydrate Chemistry (2008), 27 (3), 172-187CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
Starting from 1,2-isopropylidene-D-xylose (I), 3-methoxyoxetane δ-amino acids with D-lyxo, D-ribo, and D-arabino configurations were synthesized. The early introduction of an azide function at C-5 of I shortened the synthetic pathway. Ring contraction of the intermediate D-xylono-1,4-lactone via triflation and treatment with base led to the corresponding 3-methoxyoxetane δ-amino ester with D-lyxo configuration (II). The analogous procedure for D-ribono-1,4-lactone furnished a mixt. of D-ribo and D-arabino esters (III) and (IV). Hydrolysis of the Me esters II, III, and IV to their corresponding δ-amino acids was successful with LiOH in THF, in contrast to that of their 3-hydroxy analog analog.
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Lucas, S. D.; Rauter, A. P.; Schneider, J.; Wessel, H. P. Synthesis of 3-Fluoro-Oxetane δ-Amino Acids J. Carbohydr. Chem. 2009, 28, 431– 446 DOI: 10.1080/07328300903261562
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Synthesis of 3-fluoro-oxetane δ-amino acids
Lucas, Susana Dias; Rauter, Amelia Pilar; Schneider, Josef; Wessel, Hans Peter
Journal of Carbohydrate Chemistry (2009), 28 (7 & 8), 431-446CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
Starting from D-xylose, 2,4-anhydro-5-N-(tert-butoxycarbonyl)amino-5-deoxy-3-fluoro-D-arabinonic acid (I) (R1 = OMe; Boc = tert-butoxycarbonyl) was synthesized over 10 steps including ring contraction, fluorination, and ester hydrolysis. Bromine oxidn. of D-xylose followed by benzylidenation in a one-pot procedure led to a ca. 1:1 mixt. of lactone (II) and 2,4;3,5-dibenzylidene xylonic acid as byproduct. For the synthesis of the D-xylo deriv. (III) (R2 = OH), the chosen starting material was 1,2-O-isopropylidene-α-D-xylofuranose. A total of 14 steps including epimerization, ring contraction, fluorination, and sapon. led to the desired fluoro-oxetane δ-amino acid III (R2 = OH). Hydrolysis of the 3-fluoro-oxetane δ-amino esters I (R1 = OH) and III (R2 = OMe) by means of LiOH was successful in agreement with the results previously reported for similar 3-methoxy oxetanes, whereas chem. hydrolysis was not possible for 3-hydroxy derivs.
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Lucas, S. D.; Fischer, H.; Alker, A.; Rauter, A. P.; Wessel, H. P. Libraries on Oxetane δ-Amino Acid Scaffolds: Syntheses and Evaluation of Physicochemical and Metabolic Properties J. Carbohydr. Chem. 2011, 30, 498– 548 DOI: 10.1080/07328303.2011.609627
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Libraries on Oxetane δ-Amino Acid Scaffolds: Syntheses and Evaluation of Physicochemical and Metabolic Properties
Lucas, Susana Dias; Fischer, Holger; Alker, Andre; Rauter, Amelia P.; Wessel, Hans Peter
Journal of Carbohydrate Chemistry (2011), 30 (7-9), 498-548CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
Oxetane δ-amino acids were investigated as scaffolds to generate oxetane-based libraries. As pharmacophores, oxadiazoles and triazoles were built up on the scaffolds. Important physicochem. properties of target compds. were predicted in silico, and some physicochem. (soly., logD, pKa values, permeation through artificial membranes) and metabolic (intrinsic clearance) properties were detd. exptl. The compds. synthesized exhibited the desired ADMETox properties. From an in silico point of view, this work adds valuable information for the refinement of prediction tools.
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Skoda, E. M.; Sacher, J. R.; Kazancioglu, M. Z.; Saha, J.; Wipf, P. An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility ACS Med. Chem. Lett. 2014, 5, 900– 904 DOI: 10.1021/ml5001504
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An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility
Skoda, Erin M.; Sacher, Joshua R.; Kazancioglu, Mustafa Z.; Saha, Jaideep; Wipf, Peter
ACS Medicinal Chemistry Letters (2014), 5 (8), 900-904CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Low aq. soly. is a common challenge in drug discovery and development and can lead to inconclusive biol. assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves soly., but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly sol. drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aq. soly. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compd.
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Sprachman, M. M.; Wipf, P. A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules Assay Drug Dev. Technol. 2012, 10, 269– 277 DOI: 10.1089/adt.2011.0421
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A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules
Sprachman, Melissa M.; Wipf, Peter
Assay and Drug Development Technologies (2012), 10 (3), 269-277CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)
An oxetane-substituted sulfoxide has demonstrated potential as a dimethylsulfoxide substitute for enhancing the dissoln. of org. compds. with poor aq. solubilities. This sulfoxide may find utility in applications of library storage and biol. assays. For the model compds. studied, significant soly. enhancements were obsd. using the sulfoxide as a cosolvent in aq. media. Brine shrimp, breast cancer (MDA-MB-231), and liver cell line (HepG2) toxicity data for the new additive are also presented, in addn. to comparative IC50 values for a series of PKD1 inhibitors.
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Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design J. Med. Chem. 2011, 54, 2529– 2591 DOI: 10.1021/jm1013693
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Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design
Meanwell, Nicholas A.
Journal of Medicinal Chemistry (2011), 54 (8), 2529-2591CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering phys. properties, reducing or redirecting metab., eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compd. optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examd. are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chem. setting has been adopted by this community.
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St. Jean, D. J., Jr.; Fotsch, C. Mitigating Heterocycle Metabolism in Drug Discovery J. Med. Chem. 2012, 55, 6002– 6020 DOI: 10.1021/jm300343m
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Mitigating Heterocycle Metabolism in Drug Discovery
St. Jean, David J.; Fotsch, Christopher
Journal of Medicinal Chemistry (2012), 55 (13), 6002-6020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Extensive data from metab. studies have allowed medicinal chemists to develop general principles for reducing compd. metab. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochem. of their compds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compds. If the specific site of metab. is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. While several authors have reviewed these techniques for reducing metab., there is no review that summarizes different approaches to improving them metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compds.
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Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically Stable tert-Butyl Replacement ACS Med. Chem. Lett. 2013, 4, 514– 516 DOI: 10.1021/ml400045j
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Metabolically Stable tert-Butyl Replacement
Barnes-Seeman, David; Jain, Monish; Bell, Leslie; Ferreira, Suzie; Cohen, Scott; Chen, Xiao-Hui; Amin, Jakal; Snodgrass, Brad; Hatsis, Panos
ACS Medicinal Chemistry Letters (2013), 4 (6), 514-516CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Susceptibility to metab. is a common issue with the tert-Bu group on compds. of medicinal interest. The authors demonstrate an approach of removing all the fully Sp3 C-Hs from a tert-Bu group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-contg. analogs had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-contg. counterparts.
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Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success J. Med. Chem. 2009, 52, 6752– 6756 DOI: 10.1021/jm901241e
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Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
Lovering, Frank; Bikker, Jack; Humblet, Christine
Journal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
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Nadin, A.; Hattotuwagama, C.; Churcher, I. Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry Angew. Chem., Int. Ed. 2012, 51, 1114– 1122 DOI: 10.1002/anie.201105840
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Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry
Nadin, Alan; Hattotuwagama, Channa; Churcher, Ian
Angewandte Chemie, International Edition (2012), 51 (5), 1114-1122, S1114/1-S1114/19CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The pharmaceutical industry remains solely reliant on synthetic chem. methodol. to prep. compds. for small-mol. drug discovery programs. The importance of the physicochem. properties of these mols. in detg. their success in drug development is now well understood, but here, the authors present data suggesting that much synthetic methodol. is unintentionally predisposed to producing mols. with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger nos. of compds. from array techniques are prepd. To address this issue, the authors describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of mols. used to develop new medicines.
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Gleeson, M. P.; Hersey, A.; Montanari, D.; Overington, J. Probing the Links between in Vitro Potency, ADMET and Physicochemical Parameters Nat. Rev. Drug Discovery 2011, 10, 197– 208 DOI: 10.1038/nrd3367
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Probing the links between in vitro potency, ADMET and physicochemical parameters
Gleeson, M. Paul; Hersey, Anne; Montanari, Dino; Overington, John
Nature Reviews Drug Discovery (2011), 10 (3), 197-208CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A review. A common underlying assumption in current drug discovery strategies is that compds. with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochem. properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochem. parameters assocd. with high in vitro potency and those assocd. with desirable absorption, distribution, metab., excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on av.); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.
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Di Martino, A.; Galli, C.; Gargano, P.; Mandolini, L. Ring-Closure Reactions. Part 23. Kinetics of Formation of Three- to Seven-Membered-Ring N-Tosylazacycloalkanes. The Role of Ring Strain in Small- and Common-Sized-Ring Formation J. Chem. Soc., Perkin Trans. 2 1985, 1345– 1349 DOI: 10.1039/p29850001345
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Ring closure reactions. Part 23. Kinetics of formation of three- to seven-membered-ring N-tosylazacycloalkanes. The role of ring strain in small- and common-sized-ring formation
Di Martino, Alessandro; Galli, Carlo; Gargano, Patrizia; Mandolini, Luigi
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1985), (9), 1345-9CODEN: JCPKBH; ISSN:0300-9580.
Rates of cyclization of a series of anions derived from N-p-toluenesulfonyl-ω-bromoalkylamines to N heterocycles with 3-7 members in DMSO-H2O (99:1) were studied. The rates varied markedly with ring size in the order 5 > 3 > 6 > 7 ≈ 4. First-order rate consts. for cyclization were translated into effective molarities (EM) with ref. to an appropriate intermol. model reaction. Comparison of the present results with available literature data on SN2 ring-closure reactions leading to small- and common-size rings reveals that the ease of formation of 3-membered rings is much more structure-dependent than that of the higher homologs. This remarkable behavior is believed to parallel the unique way in which the stability of 3-membered rings is affected by structure. As a rule, the ease of cyclization appears to bear an inverted relationship to the assumed strain energy of the ring product. The apparent opposition of this rule to earlier conclusions in the literature is discussed.
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Searles, S.; Nickerson, R. G.; Witsiepe, W. K. Oxetanes. IX. Structural and Solvent Effects in the Reaction of γ–Bromoalcohols with Base J. Org. Chem. 1959, 24, 1839– 1844 DOI: 10.1021/jo01094a001
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Searles, S.; Gortatowski, M. J. Cleavage of 3-Bromo-2,2-Dimethyl-1-Propanol by Base J. Am. Chem. Soc. 1953, 75, 3030– 3031 DOI: 10.1021/ja01108a516
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Reboul, M. Oxede de Propylene Normal et Poluoxypropylenes Ann. Chim. (Paris) 1878, 14, 495– 497
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Picard, P.; Leclercq, D.; Bats, J.-P.; Moulines, J. An Efficient One-Pot Synthesis of Oxetanes from 1,3-Diols Synthesis 1981, 1981, 550– 551 DOI: 10.1055/s-1981-29523
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Rosowsky, A.; Tarbell, D. S. Synthesis and Properties of Bicyclic Oxetanes J. Org. Chem. 1961, 26, 2255– 2260 DOI: 10.1021/jo01351a026
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Balsamo, A.; Ceccarelli, G.; Crotti, P.; Macchia, F. Mechanism and Stereochemistry of Oxetane Reactions. I. Stereospecific Synthesis of the Diastereoisomeric 2-Phenyl-3-Methyloxetanes and Study of Their Configuration and Conformation by Nuclear Magnetic Resonance Spectroscopy J. Org. Chem. 1975, 40, 473– 476 DOI: 10.1021/jo00892a021
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Berkowitz, P. T.; Baum, K. Reactions of 2-Fluoro-2-Nitro-1,3-Propanediol. Trifluoromethanesulfonates and 3-Fluoro-3-Nitrooxetan J. Org. Chem. 1980, 45, 4853– 4857 DOI: 10.1021/jo01312a010
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Aftab, T.; Carter, C.; Hart, J.; Nelson, A. A Method for the Stereospecific Conversion of 1,3-Diols into Oxetanes Tetrahedron Lett. 1999, 40, 8679– 8683 DOI: 10.1016/S0040-4039(99)01840-7
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Aftab, T.; Carter, C.; Christlieb, M.; Hart, J.; Nelson, A. Stereospecific Conversion of (1R*,3S*)- and (1R*,3R*)-3-Cyclohexyl-1-Phenylpropane-1,3-Diol into the Corresponding 2,4-Disubstituted Oxetanes J. Chem. Soc. Perkin Trans. 1 2000, 711– 722 DOI: 10.1039/a909163g
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Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repič, O.; Shapiro, M. J. 1,3- Diastereoselective Reduction of β-Hydroxyketones Utilizing Alkoxydialkylboranes Tetrahedron Lett. 1987, 28, 155– 158 DOI: 10.1016/S0040-4039(00)95673-9
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1,3-syn-Diastereoselective reduction of β-hydroxy ketones utilizing alkoxydialkylboranes
Chen, Kau Ming; Hardtmann, Goetz E.; Prasad, Kapa; Repic, Oljan; Shapiro, Michael J.
Tetrahedron Letters (1987), 28 (2), 155-8CODEN: TELEAY; ISSN:0040-4039.
NaBH4 redn. of 10 β-hydroxy ketones [e.g., BuCH(OH)CH2COBu] complexed with R2BOR1 (R = Et, Bu; R1 = Me, Et, Bu, allyl, CHMe2, CMe3) gives 1,3-syn diols in 98:2 diastereomeric ratio.
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Evans, D. A.; Chapman, K. T.; Carreira, E. M. Directed Reduction of Beta-Hydroxy Ketones Employing Tetramethylammonium Triacetoxyborohydride J. Am. Chem. Soc. 1988, 110, 3560– 3578 DOI: 10.1021/ja00219a035
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Directed reduction of β-hydroxy ketones employing tetramethylammonium triacetoxyborohydride
Evans, D. A.; Chapman, K. T.; Carreira, E. M.
Journal of the American Chemical Society (1988), 110 (11), 3560-78CODEN: JACSAT; ISSN:0002-7863.
The mild reducing agent tetramethylammonium triacetoxyborohydride (I) reduces acyclic β-hydroxy ketones to their corresponding anti diols with high diastereoselectivity. α-Alkyl substitution does not significantly affect the stereoselectivity of these redns. In all cases examd., good to excellent yields of diastereomerically homogeneous diols were obtained. The mechanism of these redns. involves an acid-promoted ligand exchange of acetate for substrate alc. by the triacetoxyborohydride anion. The resultant hydride intermediate, presumably an alkoxydiacetoxyborohydride, reduces proximal ketones by intramol. hydride delivery. Ketones, β-keto esters, and β-diketones are not reduced by I in the absence of a suitably disposed hydroxyl group. Indeed both cyclic and acyclic β-hydroxy ketones may be conveniently reduced in a solvent of 1:1 acetone-acetic acid. Hydroxy diketo ester II undergoes sequential diastereoselective redns. with tetramethylammonium triacetoxyborohydride to afford a 50% isolated yield of anti-anti triol ester III in a unique stereopropagating reaction.
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Soai, K.; Niwa, S.; Yamanoi, T.; Hikima, H.; Ishizaki, M. Asymmetric Synthesis of 2-Aryl Substituted Oxetanes by Enantioselective Reduction of β-Halogenoketones Using Lithium Borohydride Modified with N,N′-Dibenzoylcystine J. Chem. Soc., Chem. Commun. 1986, 1018– 1019 DOI: 10.1039/C39860001018
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Asymmetric synthesis of 2-aryl substituted oxetanes by enantioselective reduction of β-halo ketones using lithium borohydride modified with N,N'-dibenzoylcystine
Soai, Kenso; Niwa, Seiji; Yamanoi, Takashi; Hikima, Hitoshi; Ishizaki, Miyuki
Journal of the Chemical Society, Chemical Communications (1986), (13), 1018-19CODEN: JCCCAT; ISSN:0022-4936.
Stereoselective redn. of p-RC6H4COCR12CH2Cl (R = H, F, R1 = H; R = H, R1 = Me) with LiBH4, Me3COH, and (R,R)-N,N'-dibenzoylcystine in THF at -78 to -30° for 9 h gave the corresponding (R)-p-RC6H4CH(OH)CR12CH2Cl which were cyclized with KOH to give the corresponding oxetanes I in 79-89% enantiomeric excess.
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Lo, M. M.-C.; Fu, G. C. Applications of Planar-Chiral Heterocycles in Enantioselective Catalysis: Cu(I)/bisazaferrocene-Catalyzed Asymmetric Ring Expansion of Oxetanes to Tetrahydrofurans Tetrahedron 2001, 57, 2621– 2634 DOI: 10.1016/S0040-4020(01)00082-5
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Applications of planar-chiral heterocycles in enantioselective catalysis: Cu(I)/bisazaferrocene-catalyzed asymmetric ring expansion of oxetanes to tetrahydrofurans
Lo, M. M.-C.; Fu, G. C.
Tetrahedron (2001), 57 (13), 2621-2634CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
A planar-chiral, C2-sym. bisazaferrocene ligand is shown to control the stereochem. of Cu(I)-catalyzed ring expansions of oxetanes to tetrahydrofurans.
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Brown, H. C.; Ramachandran, V. P. Asymmetric Reduction with Chiral Organoboranes Based on Alpha-Pinene Acc. Chem. Res. 1992, 25, 16– 24 DOI: 10.1021/ar00013a003
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113
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Opening of Substituted Oxetanes with H₂O₂ and Alkyl Hydroperoxides: Stereoselective Approach to 3-Peroxyalcohols and 1,2,4-Trioxepanes Org. Lett. 2002, 4, 4591– 4593 DOI: 10.1021/ol0265259
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Opening of Substituted Oxetanes with H2O2 and Alkyl Hydroperoxides: Stereoselective Approach to 3-Peroxyalcohols and 1,2,4-Trioxepanes
Dussault, Patrick H.; Trullinger, Tony K.; Noor-e-Ain, Farhana
Organic Letters (2002), 4 (26), 4591-4593CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Lewis acid-catalyzed ring opening of optically active oxetanes I [R1 = R3 = R4 = H, R2 = n-hexyl; R1 = Me, R2 = n-C16H33, Me2C:CHCH2CH2, Me2CH(CH2)3; R3, R4 = H, Me] by hydrogen peroxide proceeded regioselectively and with good to moderate stereoselectivity to furnish enantiomerically enriched 3-hydroperoxyalkanols II (R5 = H). The analogous opening using alkyl hydroperoxides R5O2H (R5 = Me3C, cumyl, tetrahydropyranyl) furnished the corresponding 3-peroxyalkanols II. II (R1 = Me; R2 = n-C16H33, Me2C:CHCH2CH2; R3 = R4 = R5 = H) were easily converted into enantiomerically enriched 1,2,4-trioxepanes III, the building blocks for antimalarials.
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Roy, B. G.; Roy, A.; Achari, B.; Mandal, S. B. A Simple One-Pot Entry to Cyclic Ethers of Varied Ring Sizes from Diols via Phosphonium Ion Induced Iodination and Base Catalyzed Williamson Etherification Tetrahedron Lett. 2006, 47, 7783– 7787 DOI: 10.1016/j.tetlet.2006.08.090
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Kawahata, Y.; Takatsuto, S.; Ikekawa, N.; Murata, M.; Omura, S. Synthesis of a New Amino Acid- Antibiotic, Oxetin and Its Three Stereoisomers Chem. Pharm. Bull. 1986, 34, 3102– 3110 DOI: 10.1248/cpb.34.3102
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There is no corresponding record for this reference.
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Wolfrom, M. L.; Hanessian, S. The Reaction of Free Carbonyl Sugar Derivatives with Organometallic Reagents. I. 6-Deoxy-L-idose and Derivatives J. Org. Chem. 1962, 27, 1800– 1804 DOI: 10.1021/jo01052a076
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The reaction of free carbonyl sugar derivatives with organometallic reagents. I. 6-Deoxy-L-idose and derivatives
Wolfrom, M. L.; Hanessian, S.
Journal of Organic Chemistry (1962), 27 (), 1800-4CODEN: JOCEAH; ISSN:0022-3263.
A stereospecific synthesis of 6-deoxy-L-idose (I) is described. It is shown that I changes to 6-deoxy-L-sorbose (II) in the presence of acid, but is otherwise stable when prepd. under neutral conditions. Reaction of 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose (III) with p-nitrobenzoyl chloride in pyridine afforded 3-O-benzyl-1,2-O-isopropylidene-5,6-di-O-(p-nitrobenzoyl)-α-D-glucofuranose (IV), m. 116-17° (Me2CO-petr. ether), [α]25D -22° (c 1.5, Me2CO). A suspension of 200 g. Pb(OAc)4 in 1.5 l. C6H6 was added gradually to 100 ml. C6H6 contg. 94 g. III, the mixt. warmed several min., filtered, the filtrate evapd. to a sirup dissolved in Et2O filtered, and the filtrate evapd. to give 79 g. sirup (92%). Distn. in a Hickman mol. pot. still and collecting the fraction, b0.07 150-5°, gave 55 g. 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (V), [α]25D -86.5° (c 2.7, EtOH-free CHCl3), strongly reducing to Fehling soln. and giving a Schiff test; V treated with semicarbazide-HCl in EtOH-H2O gave 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose semicarbazone (VI), m. 177-8°, [α]25D -50° (c 1.48, EtOH). V hydrogenated 4 hrs. over Pd-C at 65° and 400 lb./sq. in. gave 0.94 g. 1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (VII) as a sirup showing both OH and C:O absorption but lacking Ph absorption in the infrared spectrum; C:O peak diminished slightly on standing at room temp. one week; semicarbazone (VIII) m. 208-9°. V (10 g.) in 70 ml. Et2O was added dropwise over 2 hrs. to a refluxing Grignard soln. prepd. from 10.5 ml. MeI and 4.5 g. Mg turnings in 150 ml. Et2O, the mixt. refluxed another 30 min., cooled, added dropwise to a cold satd. soln. of NH4Cl (200 ml.) with vigorous stirring, the soln. extd. with Et2O, and the latter dried and evapd. under reduced pressure to a sirup that crystd. to give 6.65 g. 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (IX). The aq. soln. was evapd. to dryness, the residue extd. with CHCl3, and the soln. dried and evapd. to give 0.35 g. IX, total yield 7 g.; recrystn. from petr. ether contg. a trace of MeOH and again from Et2O-petr. ether gave 6.2 g. IX, m. 93-4°, [α]25D -63.5° (c 1.3, CHCl3). Extensive search of mother liquors from IX failed to locate any 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (X). IX (0.3 g.) in 2 ml. pyridine treated with 0.2 ml. MeSO2Cl and 2 ml. CHCl3, the mixt. poured in ice-water after standing 16 hrs. at room temp., and the solid filtered off and washed with Et2O-petr. ether (1:5) gave 0.28 g. 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-5-O-methylsulfonyl-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XI), m. 99-100° (Et2O), [α]25D -60° (c 1, CHCl3). IX (2.5 g.) in 50 ml. EtOH hydrogenated over 0.25 g. Pd-C under 300 lb./sq. in. at 65-8° 4 hrs. (the reaction failed at 28 lb./sq. in. and room temp. 24 hrs.), gave a sirup which evapd. on standing. The crystals washed with cold Et2O gave 1.1 g. 6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XII), m. 88-9°, [α]20D -7° (c 3.4, CHCl3). Acetylation of 0.15 g. XII in 1 ml. Ac2O gave after trituration of an initial sirup with Et2O-petr. ether, 0.18 g. 3,5-di-O-acetyl-6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XIII), m. 122-3° [α]23D -27° (c 2, CHCl3). IX (2.94 g.) in 12 ml. MeOH contg. 4.41 ml. N H2SO4 stirred at 70° 4 hrs., the soln. evapd., the residue in 3 ml. H2O heated an addnl. hr., the soln. neutralized with BaCO3, filtered through decolorizing C, and the filtrate evapd. gave 3-O-benzyl-6-deoxy-L-idose (XIV) as a sirup, [α]23D -11° (c 4, EtOH), Rf 0.78 in 4:1:5 BuOH-EtOH-H2O. A soln. contg. 0.85 g. XIV, 0.3 g. NaOAc, and 0.76 g. 1-benzyl-1-phenylhydrazine-HCl in 25 ml. EtOH was refluxed 3 hrs., decolorized with C, filtered, the filtrate evapd., and the residue extd. with CHCl3, washed with H2O, dried, and evapd. to a sirup that crystd. from Et2O-petr. ether to give 1.1 g. 3-O-benzyl-6-deoxy-L-idose benzylphenylhydrazone (XV), m. 120-1° (EtOH), [α]25D 44° (c 1, EtOH). XIV (0.5 g.) was heated 2 hrs. with 1.5 g. NaOAc and 2 g. PhNHNH2.HCl in 10 ml. H2O in a boiling water bath, the solvent decanted, and the residue dissolved in C6H6 and dild. with petr. ether to give 3-O-benzyl-6-deoxy-L-xylo-hexose phenylosazone (X-VI). Recrystn. from EtOH-H2O gave 0.6 g. XVI, m. 95-6°, [α]25D 36° (c 0.3, 2:3 pyridine-EtOH). XII (0.13 g.) in 0.14 ml. 0.5% H2SO4 was heated 2 hrs. at 70°, the soln. neutralized with BaCO3, treated with C, filtered, and the filtrate evapd. to a sirup which showed three spots, Rf 0.22 (zone A), 0.32 (zone B), and 0.44 (zone C) when chromatographed on paper in 4:1:5 BuOH-EtOH-H2O. Sepn. on paper sheets, elution of the resp. zones with water, and freeze-drying gave 4.9 mg. (zone A), not further studied; 12.8 mg. (zone B), and 70 mg. (zone C, II), [α]25D -24° (c 0.7, H2O). XIV (0.1 g.) in 25 ml. EtOH hydrogenated 4.5 hrs. over 10 mg. Pd-C at 500 lb./sq. in. and 65°, the mixt. filtered, and the filtrate concd. gave 80 mg. of a sirup, I, [α]25 -1.9° (c 2.5, H2O), Rf 0.32 (identical with material from zone B). Material from zone C and I (from hydrogenolysis of XIV) gave the same 6-deoxy-L-xylo-hexose phenylosazone (XVI), m. 160-6° (decompn.). I (15 mg.) (from hydrogenolysis of XIV) heated 3 hrs. in H2O contg. Amberlite IR-120 (H+) resin and the samples spotted at time intervals on paper and chromatographed, showed a new spot, C, identical with II, in addn. to the original spot B with as little as 5 min. heating.
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Nishiyama, S.; Yamamura, S.; Kato, K.; Takita, T. A Total Synthesis of Oxetanocin, a Novel Nucleoside with an Oxetane Ring Tetrahedron Lett. 1988, 29, 4743– 4746 DOI: 10.1016/S0040-4039(00)80596-1
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A total synthesis of oxetanocin, a novel nucleoside with an oxetane ring
Nishiyama, Shigeru; Yamamura, Shosuke; Kato, Kuniki; Takita, Tomohisa
Tetrahedron Letters (1988), 29 (37), 4743-6CODEN: TELEAY; ISSN:0040-4039.
Oxetanocin (I) has been synthesized starting from cis-2-butene-1,4-diol through α- or β-D-oxetanosyl acetate which has an α-(Me oxalyloxy)methyl group at C2-position.
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Nishiyama, S.; Yamamura, S.; Kato, K.; Takita, T. Synthetic Studies on Oxetanocin, a Novel Nucleoside with an Oxetane Ring Synthesis of Some Chiral D-Oxetanosyl Acylates Tetrahedron Lett. 1988, 29, 4739– 4742 DOI: 10.1016/S0040-4039(00)80595-X
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Synthetic studies on oxetanocin, a novel nucleoside with an oxetane ring. Synthesis of some chiral D-oxetanosyl acylates
Nishiyama, Shigeru; Yamamura, Shosuke; Kato, Kuniki; Takita, Tomohisa
Tetrahedron Letters (1988), 29 (37), 4739-42CODEN: TELEAY; ISSN:0040-4039.
Some chiral D-oxetanosyl acylates, e.g., I, promising synthetic precursors of oxetanocin (II), have been synthesized from D-glucose and cis-2-butene-1,4-diol, the most important step being Baeyer-Villiger oxidn. of the carbonyl group attached to C-1 of the oxetanes.
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Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L. The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol J. Am. Chem. Soc. 1997, 119, 2757– 2758 DOI: 10.1021/ja963539z
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The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol
Wender, Paul A.; Badham, Neil F.; Conway, Simon P.; Floreancig, Paul E.; Glass, Timothy E.; Houze, Jonathan B.; Krauss, Nancy E.; Lee, Daesung; Marquess, Daniel G.; McGrane, Paul L.; Meng, Wei; Natchus, Michael G.; Shuker, Anthony J.; Sutton, James C.; Taylor, Richard E.
Journal of the American Chemical Society (1997), 119 (11), 2757-2758CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A novel strategy based on an aldol cyclization which allows for the conversion of a general taxane precursor into the highly promising chemotherapeutic agent Taxol was described. This strategy allows for the synthesis of baccatins I (R = H, acetyl) starting from taxane precursor II [R1 = Si(CHMe2)3], which is available starting from (+)-verbenone. Conversion of I to Taxol has been achieved employing known three and four steps sequences, resp. This represents the shortest reported synthesis of Taxol and provides even more concise access to key analogs.
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Doi, T.; Fuse, S.; Miyamoto, S.; Nakai, K.; Sasuga, D.; Takahashi, T. A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer Chem. - Asian J. 2006, 1, 370– 383 DOI: 10.1002/asia.200600156
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A formal total synthesis of taxol aided by an automated synthesizer
Doi, Takayuki; Fuse, Shinichiro; Miyamoto, Shigeru; Nakai, Kazuoki; Sasuga, Daisuke; Takahashi, Takashi
Chemistry - An Asian Journal (2006), 1 (3), 370-383CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
A 36-step synthesis was carried out in automated synthesizers to provide a synthetic key intermediate of taxol. A key step involved a microwave-assisted alkylation reaction to construct the ABC ring system from an AC precursor. Subsequent formation of the D ring afforded (±)-baccatin III, a well-known precursor of taxol.
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Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Total Synthesis of Taxol Nature 1994, 367, 630– 634 DOI: 10.1038/367630a0
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Total synthesis of taxol
Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; et al.
Nature (London, United Kingdom) (1994), 367 (6464), 630-4CODEN: NATUAS; ISSN:0028-0836.
The total synthesis of taxol (I) from the benzofuranone II by a convergent strategy, which opens a chem. pathway for the prodn. of both I and a variety of designed taxoids is reported.
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Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M. Asymmetric Total Synthesis of Taxol Chem. - Eur. J. 1999, 5, 121– 161 DOI: 10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.3.CO;2-F
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Asymmetric total synthesis of taxol
Mukaiyama, Teruaki; Shiina, Isamu; Iwadare, Hayato; Saitoh, Masahiro; Nishimura, Toshihiro; Ohkawa, Naoto; Sakoh, Hiroki; Nishimura, Koji; Tani, Yu-Ichirou; Hasegawa, Masatoshi; Yamada, Koji; Saitoh, Katsuyuki
Chemistry - A European Journal (1999), 5 (1), 121-161CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
The asym. total synthesis of taxol was achieved by way of B to BC to ABC to ABCD ring construction. Optically active 8-membered ring enones corresponding to the B ring of taxol were synthesized in high yields from the linear precursors via intramol. aldol cyclization using SmI2. The optically active linear polyoxy compds. were obtained by way of diastereoselective aldol reaction between the protected 2,2-dimethylpentanal and the (Z)-ketene silyl acetal catalyzed by MgBr2·OEt2. This chiral pentanal was synthesized either by asym. aldol reaction of achiral aldehyde and the (Z)-ketene silyl acetal by a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde derived from L-serine and the lithium enolate derived from Me isobutyrate. Optically active bicyclo[6.4.0]dodecanone I, corresponding to the BC ring system of taxol, was prepd. from 8-membered ring enone in high yield by stereoselective Michael addn. and successive intramol. aldol cyclization. Baccatin III, the ABCD ring system of taxol, was efficiently synthesized from the BC ring system I by successive construction of the A and D rings by intramol. pinacol coupling cyclization, introduction of the C-13 hydroxyl group and an oxetane-forming reaction. The total synthesis of taxol was accomplished by dehydration condensation between a protected N-benzoylphenylisoserine and 7-TES baccatin III, prepd. from baccatin III. Taxol side chains and optically active protected N-benzoylphenylisoserines, were synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether derived from S-Et benzyloxyethanethioate.
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Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I. Enantioselective Total Synthesis of (−)-Taxol J. Am. Chem. Soc. 2000, 122, 3811– 3820 DOI: 10.1021/ja9939439
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Enantioselective Total Synthesis of (-)-Taxol
Kusama, Hiroyuki; Hara, Ryoma; Kawahara, Shigeru; Nishimori, Toshiyuki; Kashima, Hajime; Nakamura, Nobuhito; Morihira, Koichiro; Kuwajima, Isao
Journal of the American Chemical Society (2000), 122 (16), 3811-3820CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde (I) with the arom. C-ring fragment 2-bromobenzaldehyde dibenzylacetal followed by Lewis acid mediated eight-membered B-ring cyclization gave the desired ABC endo-tricarbocycle (II). The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene deriv., which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol (III) stereoselectively. For introduction of the C19-Me, the cyclopropyl ketone (IV) was prepd. via cyclopropanation of the C-ring allylic alc. or conjugate addn. of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate (V) contg. the C19-Me group. Regioselective transformation of three hydroxyl groups of V, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-oxygen functionality afforded a precursor for D-ring construction. Dihydroxylation of the allyl chloride moiety followed by basic treatment of the resulting diol gave a fully functionalized taxol skeleton (VI). Functional group manipulation of VI including attachment of the C13 side chain provided (-)-taxol.
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Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. Enantioselective Total Synthesis of Taxol J. Am. Chem. Soc. 1998, 120, 12980– 12981 DOI: 10.1021/ja9824932
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Enantioselective Total Synthesis of Taxol
Morihira, Koichiro; Hara, Ryoma; Kawahara, Shigeru; Nishimori, Toshiyuki; Nakamura, Nobuhito; Kusama, Hiroyuki; Kuwajima, Isao
Journal of the American Chemical Society (1998), 120 (49), 12980-12981CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An enantioselective total synthesis of (-)-taxol was achieved. The synthetic route is highlighted by (1) originally developed B-ring cyclization, (2) introduction of the C19-Me via reductive cleavage of the cyclopropyl ketone I, and (3) isomerization of the resulting enol to the ketone.
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Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H. First Total Synthesis of Taxol. 1. Functionalization of the B Ring J. Am. Chem. Soc. 1994, 116, 1597– 1598 DOI: 10.1021/ja00083a066
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First total synthesis of taxol. 1. Functionalization of the B ring
Holton, Robert A.; Somoza, Carmen; Kim, Hyeong Baik; Liang, Feng; Biediger, Ronald J.; Boatman, P. Douglas; Shindo, Mitsuru; Smith, Chase C.; Kim, Soekchan; et al.
Journal of the American Chemical Society (1994), 116 (4), 1597-8CODEN: JACSAT; ISSN:0002-7863.
Beginning stages of a total synthesis of the anti-tumor agent taxol were described. These stages result in the prepn. of an intermediate having three rings in which 6 stereocenters of the natural product are set. The key feature of this part of the total synthesis is control of conformation and reactivity in the bicyclo[5.3.1]undecane ring system. Thus, the diol I, a taxusin intermediate readily available from camphor, was transformed to the lactone carbonate II in 12 steps and 40% overall yield.
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Holton, R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H. First Total Synthesis of Taxol. 2. Completion of the C and D Rings Robert J. Am. Chem. Soc. 1994, 116, 1599– 1600 DOI: 10.1021/ja00083a067
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Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. Total Synthesis of Baccatin III and Taxol J. Am. Chem. Soc. 1996, 118, 2843– 2859 DOI: 10.1021/ja952692a
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Total Synthesis of Baccatin III and Taxol
Danishefsky, Samuel J.; Masters, John J.; Young, Wendy B.; Link, J. T.; Snyder, Lawrence B.; Magee, Thomas V.; Jung, David K.; Isaacs, Richard C. A.; Bornmann, William G.; et al.
Journal of the American Chemical Society (1996), 118 (12), 2843-59CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An intramol. Heck reaction (diene I to pentacycle II) serves as the key step in the total synthesis of the titled compds. III (R = H, R2). The synthetic route is based on utilizing the Wieland-Miescher ketone (IV) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to A ring precursor, 2,2,4-trimethyl-1,3-cyclohexanedione. Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
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Fukaya, K.; Kodama, K.; Tanaka, Y.; Yamazaki, H.; Sugai, T.; Yamaguchi, Y.; Watanabe, A.; Oishi, T.; Sato, T.; Chida, N. Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis Org. Lett. 2015, 17, 2574– 2577 DOI: 10.1021/acs.orglett.5b01174
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Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis
Fukaya, Keisuke; Kodama, Keisuke; Tanaka, Yuta; Yamazaki, Hirohisa; Sugai, Tomoya; Yamaguchi, Yu; Watanabe, Ami; Oishi, Takeshi; Sato, Takaaki; Chida, Noritaka
Organic Letters (2015), 17 (11), 2574-2577CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-D-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate (I). A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.
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Hirai, S.; Utsugi, M.; Iwamoto, M.; Nakada, M. Formal Total Synthesis of (−)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation Chem. - Eur. J. 2015, 21, 355– 359 DOI: 10.1002/chem.201404295
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Formal Total Synthesis of (-)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation
Hirai, Sho; Utsugi, Masayuki; Iwamoto, Mitsuhiro; Nakada, Masahisa
Chemistry - A European Journal (2015), 21 (1), 355-359CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A formal total synthesis of (-)-taxol by a convergent approach utilizing Pd-catalyzed intramol. alkenylation is described. Formation of the eight-membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd-catalyzed intramol. alkenylation of a Me ketone affording the cyclized product in excellent yield (97%), indicating the high efficiency of the Pd-catalyzed intramol. alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5-hydride shift, generating the C3 stereogenic center and subsequently forming the C1-C2 benzylidene, was discovered and utilized in the prepn. of a substrate for the Pd-catalyzed reaction.
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Zefirova, O. N.; Nurieva, E. V.; Lemcke, H.; Ivanov, A. A.; Zyk, N. V.; Weiss, D. G.; Kuznetsov, S. A.; Zefirov, N. S. Design, Synthesis and Bioactivity of Simplified Taxol Analogues on the Basis of bicyclo[3.3.1]nonane Derivatives Mendeleev Commun. 2008, 18, 183– 185 DOI: 10.1016/j.mencom.2008.07.003
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Design, synthesis and bioactivity of simplified taxol analogs on the basis of bicyclo[3.3.1]nonane derivatives
Zefirova, Olga N.; Nurieva, Evgeniya V.; Lemcke, Heiko; Ivanov, Andrei A.; Zyk, Nikolai V.; Weiss, Dieter G.; Kuznetsov, Sergei A.; Zefirov, Nikolai S.
Mendeleev Communications (2008), 18 (4), 183-185CODEN: MENCEX; ISSN:0959-9436. (Elsevier B.V.)
Four specially designed bicyclo[3.3.1]nonane derivs. I [R = Ph, R1 = H, R2 = H; R = Ph, R1 = OCOPh, R2 = H; R = Ph, R1 = H, R2 = CH2OAc; R = OCMe3, R1 = H, R2 = 3-oxetanyloxycarbonyl] were synthesized and found to be cytotoxic at micromolar concns. against A549 human lung carcinoma cells and to cause slight non-specific tubulin aggregation.
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Fuji, K.; Watanabe, Y.; Ohtsubo, T.; Nuruzzaman, M.; Hamajima, Y.; Kohno, M. Synthesis of Extremely Simplified Compounds Possessing the Key Pharmacophore Units of Taxol, Phenylisoserine and Oxetane Moieties Chem. Pharm. Bull. 1999, 47, 1334– 1337 DOI: 10.1248/cpb.47.1334
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Synthesis of extremely simplified compounds possessing the key pharmacophore units of taxol, phenylisoserine and oxetane moieties
Fuji, Kaoru; Watanabe, Yukari; Ohtsubo, Tadamune; Nuruzzaman, Mohammad; Hamajima, Yoshio; Kohno, Michiaki
Chemical & Pharmaceutical Bulletin (1999), 47 (9), 1334-1337CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
Straight-chain compds. having a phenylisoserine unit and an oxetane ring at the α- and ω-position, resp., were prepd. as simplified analogs of taxol. Their most stable conformations were calcd. using mol. mechanics. None of these compds. showed promising tubulin inhibitory activity.
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Chen, X.-X.; Gao, F.; Wang, Q.; Huang, X.; Wang, D. Design, Synthesis and Biological Evaluation of Paclitaxel-Mimics Possessing Only the Oxetane D-Ring and Side Chain Structures Fitoterapia 2014, 92, 111– 115 DOI: 10.1016/j.fitote.2013.10.015
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Design, synthesis and biological evaluation of paclitaxel-mimics possessing only the oxetane D-ring and side chain structures
Chen, Xing-Xiu; Gao, Feng; Wang, Qi; Huang, Xing; Wang, Dan
Fitoterapia (2014), 92 (), 111-115CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)
Two spiro paclitaxel-mimics consisting only of an oxetane D-ring and a C-13 side chain were designed and synthesized on the basis of anal. of structure-activity relationships of paclitaxel. In vitro microtubule-stabilizing and antiproliferative assays indicated a moderate weaker activity of the mimics than paclitaxel, but which still represented the first example of simplified paclitaxel analogs with significant antitumor activity.
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Ye, Y.; Zheng, C.; Fan, R. Solvent-Controlled Oxidative Cyclization for Divergent Synthesis of Highly Functionalized Oxetanes and Cyclopropanes Org. Lett. 2009, 11, 3156– 3159 DOI: 10.1021/ol9012102
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Solvent-Controlled Oxidative Cyclization for Divergent Synthesis of Highly Functionalized Oxetanes and Cyclopropanes
Ye, Yang; Zheng, Chen; Fan, Renhua
Organic Letters (2009), 11 (14), 3156-3159CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
An efficient solvent-controlled oxidative cyclization of Michael adducts of malonates with chalcones with the combination of iodosobenzene and tetrabutylammonium iodide is reported. Highly functionalized oxetanes and cyclopropanes were divergently synthesized in moderate to excellent yields with high diastereoselectivity.
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Miao, C.-B.; Zhang, M.; Tian, Z.-Y.; Xi, H.-T.; Sun, X.-Q.; Yang, H.-T. Base-Controlled Selective Conversion of Michael Adducts of Malonates with Enones in the Presence of Iodine J. Org. Chem. 2011, 76, 9809– 9816 DOI: 10.1021/jo201879t
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135
Davies, A. T.; Slawin, A. M. Z.; Smith, A. D. Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes Chem. - Eur. J. 2015, 21, 18944– 19848 DOI: 10.1002/chem.201504256
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Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes
Davies, Alyn T.; Slawin, Alexandra M. Z.; Smith, Andrew D.
Chemistry - A European Journal (2015), 21 (52), 18944-18948CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The N-heterocyclic carbene (NHC) catalyzed redox formal [2+2] cycloaddn. between α-aroyloxyaldehydes and perfluoroketones, followed by ring-opening in situ delivers a variety of perfluorinated β-hydroxycarbonyl compds. in good yield, and excellent diastereoselectivity and enantioselectivity. Through a reductive work-up and subsequent cyclization, this protocol offers access to highly substituted fluorinated oxetanes in two steps and in high ee. Under optimized conditions the synthesis of the target compds. was achieved using (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazinium chloride as a catalyst. Starting materials included 2,2,3,3,3-pentafluoro-1-phenyl-1-propanone 2,2,3,3,4,4,5,5,5-nonafluoro-1-phenyl-1-pentanone, trifluoroacetone, 2-[(4-nitrobenzoyl)oxy]propanal, α-[(4-nitrobenzoyl)oxy]benzenepropanal and amine derivs. Oxetane derivs. included 3-alkyl-2-(phenyl)-2-(perfluoroalkyl)oxetane.
136
Behrendt, J. M.; Bala, K.; Golding, P.; Hailes, H. C. Oxetane Synthesis via Cyclisation of Aryl Sulfonate Esters on Polystyrene and PEG Polymeric Supports Tetrahedron Lett. 2005, 46, 643– 645 DOI: 10.1016/j.tetlet.2004.11.138
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137
Vigo, D.; Stasi, L.; Gagliardi, S. Synthesis of 3,3-Disubstituted Oxetane Building Blocks Tetrahedron Lett. 2011, 52, 565– 567 DOI: 10.1016/j.tetlet.2010.11.118
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138
Boyd, S.; Davies, C. D. A New and Versatile Synthesis of 3-Substituted Oxetan-3-yl Methyl Alcohols Tetrahedron Lett. 2014, 55, 4117– 4119 DOI: 10.1016/j.tetlet.2014.06.024
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139
Searles, S.; Nickerson, R. G.; Witsiepe, W. K. Oxetanes. IX. Structural and Solvent Effects in the Reaction of γ-Bromoalcohols with Base J. Org. Chem. 1959, 24, 1839– 1844 DOI: 10.1021/jo01094a001
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140
Davis, O. A.; Bull, J. A. Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-Catalyzed O-H Insertion and C-C Bond-Forming Cyclization Angew. Chem., Int. Ed. 2014, 53, 14230– 14234 DOI: 10.1002/anie.201408928
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140
Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-Catalyzed O-H Insertion and C-C Bond-Forming Cyclization
Davis, Owen A.; Bull, James A.
Angewandte Chemie, International Edition (2014), 53 (51), 14230-14234CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl-substituted oxetanes and fused oxetane bicycles. Enantioenriched alcs. provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chem.
141
Nagai, M.; Kato, K.; Takita, T.; Nishiyama, S.; Yamamura, S. A Facile and Practical Synthesis of the Derivatives of 1-O-Acetyl-2-Deoxy-2-Hydroxymethyl-D-Erythrooxetanose, a Key Sugar Moiety for the Synthesis of Oxetanosyl-N-Glycoside Tetrahedron Lett. 1990, 31, 119– 120 DOI: 10.1016/S0040-4039(00)94349-1
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A facile and practical synthesis of the derivatives of 1-O-acetyl-2-deoxy-2-hydroxymethyl-D-erythrooxetanose, a key sugar moiety for the synthesis of oxetanosyl-N-glycoside
Nagai, Masashi; Kato, Kuniki; Takita, Tomohisa; Nishiyama, Shigeru; Yamamura, Shosuke
Tetrahedron Letters (1990), 31 (1), 119-20CODEN: TELEAY; ISSN:0040-4039.
Intramol. cyclization of the epoxy-alc. I with KOH in aq. DMSO gave predominantly the oxetane II (R = CH2Ph, R1 = CHMeOH), which could be transformed into 1-O-acetyl-D-oxetanose II (R = Bz, R1 = OAc).
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Nagai, M.; Kato, K.; Takita, T.; Nishiyama, S.; Yamamura, S. An Improved, Practical Synthesis of the Derivatives of 1-O-Acetyl-2- Deoxy-2-Hydroxymethyl-D-Erythrooxetanose, a Key Sugar Moiety for the Synthesis of Oxetanosyl-N-Glycoside Tetrahedron 1990, 46, 7703– 7710 DOI: 10.1016/S0040-4020(01)90066-3
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143
Chung, S.-K.; Ban, S. H.; Kim, S. H.; Woo, S. H. Review: Design, Synthesis and Bioactivities of Heterocyclic Lipids as Platelet Activating Factor Antagonists Korean J. Med. Chem. 1996, 6 (2) 294– 302
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143
Design, synthesis and bioactivities of heterocyclic lipids as platelet activating factor antagonists
Chung, Sung-Kee; Ban, Su Ho; Kim, Si Hwan; Woo, Soon Hyung
Korean Journal of Medicinal Chemistry (1996), 6 (2), 294-302CODEN: KJMCE7; ISSN:1225-0058. (Korean Chemical Society)
Title compds. such as I [X = (CH2)n, n = 1-4; O, AcN], II [X = CH2CH2, O, S; T = CO; n = 4, 5; N(Het) = pyridine, thiazole, quinoline], and III (X = CH2, O, S, NAc, NBz; Y = Cl, I) were prepd. and tested for their ability to displace [3H]-PAF from its receptor in rabbit platelet membranes and to inhibit PAF-induced aggregation of rabbit platelets.
144
Wishka, D. G.; Beagley, P.; Lyon, J.; Farley, K. A.; Walker, D. P. A Concise Synthesis of 6-Oxa-3-azabicyclo[31.1]heptane Hydrotosylate Synthesis 2011, 2011, 2619– 2624 DOI: 10.1055/s-0030-1260116
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145
Birman, V. B.; Danishefsky, S. J. The Total Synthesis of (±)-Merrilactone A J. Am. Chem. Soc. 2002, 124, 2080– 2081 DOI: 10.1021/ja012495d
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145
The total synthesis of (±)-merrilactone A
Birman, Vladimir B.; Danishefsky, Samuel J.
Journal of the American Chemical Society (2002), 124 (10), 2080-2081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The total synthesis of the (±)-merrilactone A (I) has been accomplished in 20 steps. The key step is a free radical cyclization of vinyl bromide II [R = CH2CH2C(:CH2)Br] to afford III. The synthesis also features an efficient Diels-Alder reaction of 2,3-dimethylmaleic anhydride with 1-(tert-butyldimethylsiloxy)-butadiene. The oxetane moiety of I is fashioned via a Payne-like rearrangement of a hydroxyepoxide (see IV → I).
146
Inoue, M.; Sato, T.; Hirama, M. Asymmetric Total Synthesis of (−)-Merrilactone A: Use of a Bulky Protecting Group as Long-Range Stereocontrolling Element Angew. Chem., Int. Ed. 2006, 45, 4843– 4848 DOI: 10.1002/anie.200601358
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Asymmetric total synthesis of (-)-merrilactone A: use of a bulky protecting group as long-range stereocontrolling element
Inoue, Masayuki; Sato, Takaaki; Hirama, Masahiro
Angewandte Chemie, International Edition (2006), 45 (29), 4843-4848CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Designer elegance: The transannular aldol reaction of a cyclooctene diketone is the key step in this total synthesis of the natural enantiomer of merrilactone A, I. The configuration of the two stereocenters generated in the formation of the central bicyclo[3.3.0]octane framework of the natural product was established using a specially designed bulky protecting group.
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Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.; Zhai, H. Total Synthesis of (±)-Merrilactone A Angew. Chem., Int. Ed. 2012, 51, 5897– 5899 DOI: 10.1002/anie.201200378
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147
Total Synthesis of (±)-Merrilactone A
Chen, Jianwei; Gao, Peng; Yu, Fangmiao; Yang, Yang; Zhu, Shizheng; Zhai, Hongbin
Angewandte Chemie, International Edition (2012), 51 (24), 5897-5899, S5897/1-S5897/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
An efficient total synthesis of (±)-Merrilactone A (I) was accomplished in fifteen reaction steps for the shortest sequence from an allyl alc. Key features include Johnson-Claisen rearrangement and the subsequent deprotection-lactonization to generate the A ring, intramol. hetero-Pauson-Khand reaction to construct the B and D rings in one step, and vinylogous Mukaiyama-Michael reaction and reductive carbonyl-alkene coupling to assemble the C ring.
148
Mehta, G.; Singh, S. R. Total Synthesis of (±)-Merrilactone A Angew. Chem., Int. Ed. 2006, 45, 953– 955 DOI: 10.1002/anie.200503618
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148
Total synthesis of (±)-merrilactone A
Mehta, Goverdhan; Singh, S. Robindro
Angewandte Chemie, International Edition (2006), 45 (6), 953-955CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A stereoselective total synthesis of the pentacyclic sesquiterpenoid (±)-merrilactone A (I) starting from 4,5-dimethyl-4-cyclopentene-1,3-dione was achieved. Merrilactone A has exhibited impressive neurotrophic activity (no biol. testing data presented), and it may be important for the development of therapeutic drugs for neurodegenerative disorders.
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He, W.; Huang, J.; Sun, X.; Frontier, A. J. Total Synthesis of (±)-Merrilactone A via Catalytic Nazarov Cyclization J. Am. Chem. Soc. 2007, 129, 498– 499 DOI: 10.1021/ja068150i
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149
Total Synthesis of (±)-Merrilactone A via Catalytic Nazarov Cyclization
He, Wei; Huang, Jie; Sun, Xiufeng; Frontier, Alison J.
Journal of the American Chemical Society (2007), 129 (3), 498-499CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The total synthesis of Merrilactone A (a neurotrophic agent) has been achieved. In the approach reported, simultaneous creation of the C-4 and C-5 stereocenters was accomplished stereospecifically using an unprecedented variant of the Nazarov cyclization. Addnl. studies focused upon this Lewis acid-catalyzed cyclization of a silyloxyfuran-contg. intermediate are presented.
150
Inoue, M.; Sato, T.; Hirama, M. Total Synthesis of (±)-Merrilactone A J. Am. Chem. Soc. 2003, 125, 10772– 10773 DOI: 10.1021/ja036587+
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151
Servrin, M.; Krief, A. Regioselective and [C,C] Connective Routes to Oxetane and Tetrahydrofuranes Tetrahedron Lett. 1980, 21, 585– 586 DOI: 10.1016/S0040-4039(01)85563-5
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152
Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. Reaction of Dimethyloxosulfonium Methylide with Epoxides. Preparation of Oxetanes J. Org. Chem. 1983, 48, 5133– 5134 DOI: 10.1021/jo00173a072
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152
Reaction of dimethyloxosulfonium methylide with epoxides. Preparation of oxetanes
Okuma, Kentaro; Tanaka, Yoshihiko; Kaji, Shinji; Ohta, Hiroshi
Journal of Organic Chemistry (1983), 48 (25), 5133-4CODEN: JOCEAH; ISSN:0022-3263.
Reaction of Me2S+(O)C-H2 with epoxides in Me3COH gave corresponding oxetanes I [R = H, Me, Ph; R1 = Ph, 4-ClC6H4, RR1 = (CH2)5] in 83-94% yields. Oxetanes were also synthesized in 80-97% yields by the reaction of 2-fold excess of Me2S+(O)C-H2 with RR1CO [R = H, Me, Et, Ph; R1 = Ph, 4-ClC6H4, 4-MeC6H4; RR1 = (CH2)5, MeCH(CH2CH2)2, Me2CCH(CH2CH2)2]. This is the first example of the double methylene transfer reaction of the ylide.
153
Welch, S. C.; Prakasa Rao, A. S. C. A Convenient One-Step Synthesis of 2,2-Disubstituted Oxetanes from Ketones J. Am. Chem. Soc. 1979, 101, 6135– 6136 DOI: 10.1021/ja00514a053
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153
A convenient one-step synthesis of 2,2-disubstituted oxetanes from ketones
Welch, Steven C.; Rao, A. S. C. Prakasa
Journal of the American Chemical Society (1979), 101 (20), 6135-6CODEN: JACSAT; ISSN:0002-7863.
A convenient and facile one-step synthesis of 2,2-disubstituted oxetanes from ketones utilizing the sodium anion of dimethyl-N-(p-toluenesulfonyl)sulfoximine in Me2SO is presented. Yields were 46-96%. Fifteen ketones, e.g., estrone 3-Me ether, camphor, 4-tert-butylcyclohexanone, 3-cholestanone, norcamphor, bicyclo[3.3.1]nonan-9-one, cyclohexanone and 2-tridecanone were converted to the corresponding oxetanes.
154
Welch, S. C.; Prakasa Rao, A. S. C.; Lyon, J. T.; Assercq, J. M. Synthesis of 2,2-Disubstituted Oxetanes from Ketones Wigh S-Methyl-S-(sodiomethyl)-N-(4-Tolylsulfonyl)sulfoximine J. Am. Chem. Soc. 1983, 105, 252– 257 DOI: 10.1021/ja00340a019
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155
Fitton, A. O.; Hill, J.; Jane, D. E.; Millar, R. Synthesis of Simple Oxetanes Carrying Reactive 2-Substituents Synthesis 1987, 1987, 1140– 1142 DOI: 10.1055/s-1987-28203
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156
Butova, E. D.; Barabash, A. V.; Petrova, A. A.; Kleiner, C. M.; Schreiner, P. R.; Fokin, A. A. Stereospecific Consecutive Epoxide Ring Expansion with Dimethylsulfoxonium Methylide J. Org. Chem. 2010, 75, 6229– 6235 DOI: 10.1021/jo101330p
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156
Stereospecific Consecutive Epoxide Ring Expansion with Dimethylsulfoxonium Methylide
Butova, Ekaterina D.; Barabash, Anastasiya V.; Petrova, Anna A.; Kleiner, Christian M.; Schreiner, Peter R.; Fokin, Andrey A.
Journal of Organic Chemistry (2010), 75 (18), 6229-6235CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Consecutive ring-expansion reactions of oxiranes with dimethylsulfxonium methylide were studied exptl. and modeled computationally at the d. functional theory (DFT) and second-order Moller-Plesset (MP2) levels of theory utilizing a polarizable continuum model (PCM) to account for solvent effects. While the epoxide to oxetane ring expansion requires 13-17 kcal mol-1 activation and occurs at elevated temps., the barriers for the ring expansions to oxolanes are higher (ca. 25 kcal mol-1) and require heating to 125 °C. Further expansions of these oxolanes to the six-membered oxanes are hampered by high barriers (ca. 40 kcal mol-1). We obsd. the complete conservation of the enantiomeric purities for the nucleophilic ring expansions of enantiomeric 2-mono- and 2,2-disubstituted epoxides and oxetanes with dimethylsulfoxonium methylide. This is a convenient general approach for the high-yielding prepn. of optically active four- and five-membered cyclic ethers, e.g I and II, from oxiranes.
157
Fritz, S. P.; Moya, J. F.; Unthank, M. G.; McGarrigle, E. M.; Aggarwal, V. K. An Efficient Synthesis of Azetidines with (2-Bromoethyl)sulfonium Triflate Synthesis 2012, 44, 1584– 1590 DOI: 10.1055/s-0031-1290951
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157
An efficient synthesis of azetidines with (2-bromoethyl)sulfonium triflate
Fritz, Sven P.; Moya, Juan F.; Unthank, Matthew G.; McGarrigle, Eoghan M.; Aggarwal, Varinder K.
Synthesis (2012), 44 (10), 1584-1590CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
Easily accessible arylglycine derivs. were cyclized to azetidines by using com. available (2-bromoethyl)sulfonium triflate in a simple and mild procedure. The high-yielding reaction has a relatively broad scope and was extended to the synthesis of an oxetane.
158
Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Catalytic Asymmetric Synthesis of 2,2-Disubstituted Oxetanes From Ketones by Using a One-Pot Sequential Addition of Sulfur Ylide Angew. Chem., Int. Ed. 2009, 48, 1677– 1680 DOI: 10.1002/anie.200805473
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158
Catalytic asymmetric synthesis of 2,2-disubstituted oxetanes from ketones by using a one-pot sequential addition of sulfur ylide
Sone, Toshihiko; Lu, Gang; Matsunaga, Shigeki; Shibasaki, Masakatsu
Angewandte Chemie, International Edition (2009), 48 (9), 1677-1680CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Enantiopure 2-Me-2-R-substituted oxetanes (R = n-octyl, 9-decenyl, cyclohexyl, Ph, 4-ClC6H4, 4-FC6H4, PhCH2CH2, 2-naphthyl) were synthesized from the corresponding ketones RCOMe and dimethyloxosulfonium methylide via one-pot double methylene transfer catalyzed by a heterobimetallic La/Li complex. Chiral amplification in the second step was the key to obtain oxetanes in high enantiomeric excess.
159
Hintzer, K.; Koppenhoefer, B.; Schurig, V. Access to (S)-2-Methyloxetane and the Precursor (S)-1,3-Butanediol of High Enantiomeric Purity J. Org. Chem. 1982, 47, 3850– 3854 DOI: 10.1021/jo00141a009
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160
Jenkinson, S. F.; Fleet, G. W. J. Oxetanes from the Ring Contraction of α-Triflates from γ-Lactones: Oxetane Nucleosides and Oxetane Amino Acids Chimia 2011, 65, 71– 75 DOI: 10.2533/chimia.2011.71
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160
Oxetanes from the ring contraction of α-triflates of γ-lactones: oxetane nucleosides and oxetane amino acids
Jenkinson, Sarah F.; Fleet, George W. J.
Chimia (2011), 65 (1-2), 71-75CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
A review with refs. α-Triflates of γ-lactones with potassium carbonate in methanol give efficient contraction of the ring to oxetane-1-carboxylates in which the oxygen substituent at C(3) of the oxetane is predominantly trans to the carboxylate at C(2), regardless of the stereochem. of the starting triflate. The limitations of the procedure are discussed and compared with analogous reactions for the prepn. of THF carboxylates. The potential of the contraction in the prepn. of oxetane nucleosides (such as oxetanocin) and oxetane sugar amino acids (analogs of oxetin) as peptidomimetics with pre-disposition to form secondary structural motifs is illustrated.
161
Austin, G. N.; Fleet, G. W. J.; Peach, J. M.; Prout, K.; Son, J. C. Chiral Oxetanes from Sugar Lactones: Synthesis of Derivatives of 3,5-Anhydro-1,2-O-Isopropylidine-α-D-Glucuronic Acid and of 3,5-Anhydro-1,2-O-Isopropylidine-β-L-Iduronic Acid Tetrahedron Lett. 1987, 28, 4741– 4744 DOI: 10.1016/S0040-4039(00)96614-0
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Chiral oxetanes from sugar lactones: synthesis of derivatives of 3,5-anhydro-1,2-O-isopropylidene-α-D-glucuronic acid and of 3,5-anhydro-1,2-O-isopropylidene-β-L-iduronic acid
Austin, G. N.; Fleet, G. W. J.; Peach, J. M.; Prout, K.; Son, Jong Chan
Tetrahedron Letters (1987), 28 (40), 4741-4CODEN: TELEAY; ISSN:0040-4039.
Ring contraction reactions of triflates of α-hydroxy-γ-lactones provide an approach to the synthesis of chiral polyfunctionalized oxetanes from sugars. Treatment of 1,2-O-isopropylidene-5-O-trifluoromethanesulfonyl-α-D-glucuronolactone (I) with benzylamine or with K2CO3 in MeOH gave ring contraction reactions to form oxetanes, e.g., II, in good yield.
162
Dax, K.; Weidmann, H. Reactions of D-Glucofuranurono-6,3-Lactone Adv. Carbohydr. Chem. Biochem. 1976, 33, 189– 234 DOI: 10.1016/S0065-2318(08)60282-6
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163
Bashyal, B. P.; Chow, H.-F.; Fellows, L. E.; Fleet, G. W. J. The Synthesis of Polyhydroxylated Amino Acids from Glucuronolactone: Enantiospecific Syntheses of 2S, 3R, 4R, 5S-Trihydroxypipecolic Acid, 2R, 3R, 4R, 5S-Trihydroxypipecolic Acid and 2R, 3R, 4R-Dihydroxyproline Tetrahedron 1987, 43, 415– 422 DOI: 10.1016/S0040-4020(01)89972-5
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164
Csuk, R.; Honig, H.; Nimp, J.; Weidmann, H. A Facile Synthesis of 1,2,-O-Isopropylidene-B-L-Idofuranurono-6,3-Lactone Tetrahedron Lett. 1980, 21, 2135– 2136 DOI: 10.1016/S0040-4039(00)78978-7
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165
Barton, D. H. R.; Crich, D.; Motherwell, W. B. The Invention Of New Radical Chain Reactions. Part VIII. Radical Chemistry Of Thiohydroxamic Esters; A New Method For The Generation Of Carbon Radicals From Carboxylic Acids Tetrahedron 1985, 41, 3901– 3924 DOI: 10.1016/S0040-4020(01)97173-X
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165
The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters; a new method for the generation of carbon radicals from carboxylic acids
Barton, Derek H. R.; Crich, David; Motherwell, William B.
Tetrahedron (1985), 41 (19), 3901-24CODEN: TETRAB; ISSN:0040-4020.
The aliph. and alicyclic esters of N-hydroxypyridine-2-thione were reduced by Bu3SnH in a radical chain reaction to furnish noralkanes. In the absence of the stannane, a smooth decarboxylative rearrangement occurred to give 2-substituted thiopyridines. Radical intermediates reacted with Me3CSH to form noralkane and 2-pyridyl tert-Bu disulfide. The carbon radicals were also captured by halogen atom transfer to give noralkyl chlorides, bromides, and iodides. In the presence of O and Me3CSH, the corresponding noralkyl hydroperoxides were formed by another radical chain reaction.
166
Fleet, G. W. J.; Son, J. C.; Peach, J. M.; Hamor, T. A. Synthesis and X-Ray Crystal Structure of a Stable α-Chlorooxetane Tetrahedron Lett. 1988, 29, 1449– 1450 DOI: 10.1016/S0040-4039(00)80321-4
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167
Fleet, G. W. J.; Son, J. C.; Vogt, K.; Peach, J. M.; Hamor, T. A. Reaction of Adenine with an α-Chlorooxetane: An Approach to the Synthesis of Oxetane Nucleosides Tetrahedron Lett. 1988, 29, 1451– 1452 DOI: 10.1016/S0040-4039(00)80322-6
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168
Witty, D. R.; Fleet, G. W. J.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Ring Contraction of 2-O-Trifluoromethanesulphonates of α-Hydroxy-γ-Lactones to Oxetane Carboxylic Esters Tetrahedron Lett. 1990, 31, 4787– 4790 DOI: 10.1016/S0040-4039(00)97734-7
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Witty, D. R.; Fleet, G. W. J.; Choi, S.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Ring Contraction of 3-Deoxy-2-O-trifluoromethanesulphonates of α-Hydroxy-γ-Lactones to Oxetanes Tetrahedron Lett. 1990, 31, 6927– 6930 DOI: 10.1016/S0040-4039(00)97209-5
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Ring contraction of 3-deoxy-2-O-trifluoromethanesulfonates of α-hydroxy-γ-lactones to oxetanes
Witty, D. R.; Fleet, G. W. J.; Choi, S.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J.
Tetrahedron Letters (1990), 31 (47), 6927-30CODEN: TELEAY; ISSN:0040-4039.
α-Triflates of 3-deoxy-1,4-lactones bearing H or alkyl substituents in the 3-position undergo ring contraction to Me oxetane-2-carboxylates on treatment with K2CO3-MeOH.
170
Wilson, F. X.; Fleet, G. W. J.; Vogt, K.; Wang, Y.; Witty, D. R.; Choi, S.; Storer, R.; Myers, P. L.; Wallis, C. J. Synthesis of Oxetanocin Tetrahedron Lett. 1990, 31, 6931– 6934 DOI: 10.1016/S0040-4039(00)97210-1
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Synthesis of oxetanocin
Wilson, F. X.; Fleet, G. W. J.; Vogt, K.; Wang, Y.; Witty, D. R.; Choi, S.; Storer, R.; Myers, P. L.; Wallis, C. J.
Tetrahedron Letters (1990), 31 (47), 6931-4CODEN: TELEAY; ISSN:0040-4039.
Oxetanocin (I) and its α-epimer were prepd. by reaction of adenine with a protected 3-hydroxymethyl-2-chlorooxetane. Attempts to synthesize C-2' alkyl analogs of oxetanocin by analogous reactions indicate the limitation of this strategy for the synthesis of oxetane nucleosides. I had a virucidal ED50 against HIV of 0.5-1.5 μg/mL whereas its epimer was inactive.
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Wilson, F. X.; Fleet, G. W. J.; Witty, D. R.; Vogt, K.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Synthesis of the Oxetane Nucleosides α- and β-Noroxetanocin Tetrahedron: Asymmetry 1990, 1, 525– 526 DOI: 10.1016/S0957-4166(00)80540-6
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Wang, Y.; Fleet, G. W. J.; Storer, R.; Myers, P. L.; Wallis, C. J.; Doherty, O.; Watkin, D. J.; Vogt, K.; Witty, D. R.; Wilson, F. X.; Peach, J. M. Synthesis of the Potent Antiviral Oxetane Nucleoside Epinooxetanocin from D-Lyxonolactone Tetrahedron: Asymmetry 1990, 1, 527– 530 DOI: 10.1016/S0957-4166(00)80541-8
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Saksena, A. K.; Ganguly, A. K.; Girijavallabhan, V. M.; Pike, R. E.; Chen, Y.-T.; Puar, M. S. Ring Contraction Reactions of 2-O-Methanesulfonates of α-Hydroxy-γ-Lactones in Aqueous Medium to Oxetane-2-Carboxylic Acids: A Convenient Synthesis of 3′-O-Methyloxetanocin and a Formal Synthesis of Oxetanocin Tetrahedron Lett. 1992, 33, 7721– 7724 DOI: 10.1016/0040-4039(93)88027-G
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Gumina, G.; Chu, C. K. Synthesis of L-Oxetanocin Org. Lett. 2002, 4, 1147– 1149 DOI: 10.1021/ol025562x
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Synthesis of L-Oxetanocin
Gumina, Giuseppe; Chu, Chung K.
Organic Letters (2002), 4 (7), 1147-1149CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Hitherto unknown L-oxetanocin has been synthesized from L-xylose in 16 steps via a ribonolactone deriv. L-Oxetanocin showed no activity up to 100 mM against HIV-1.
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Wang, Y.; Fleet, G. W. J.; Wilson, F. X.; Storer, R.; Wallis, C. J.; Doherty, O.; Watkin, D. J.; Vogt, K.; Witty, D. R.; Peach, J. M. Oxetane Nucleosides with Fluorine and Azide Substituents: Nucleophilic Displacements on an Oxetane Ring Tetrahedron Lett. 1991, 32, 1675– 1678 DOI: 10.1016/S0040-4039(00)74302-4
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Johnson, S. W.; Angus, D.; Taillefumier, C.; Jones, J. H.; Watkin, D. J.; Floyd, E.; Buchanan, J. G.; Fleet, G. W. J. Two Epimerisations In The Formation Of Oxetanes From L-Rhamnose: Towards Oxetane-Containing Peptidomimetics Tetrahedron: Asymmetry 2000, 11, 4113– 4125 DOI: 10.1016/S0957-4166(00)00360-8
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Barker, S. F.; Angus, D.; Taillefumier, C.; Probert, M. R.; Watkin, D. J.; Watterson, M. P.; Claridge, T. D. W.; Hungerford, N. L.; Fleet, G. W. J. cis- and trans-3-Azido-Oxetane-2-Carboxylate Scaffolds: Hexamers Of Oxetane cis-B-Amino Acids Tetrahedron Lett. 2001, 42, 4247– 4250 DOI: 10.1016/S0040-4039(01)00660-8
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Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Jones, J. H.; Fleet, G. W. J.; Taillefumier, C. Oxetane Cis- and Trans-β-Amino-Acid Scaffolds from L-Rhamnose by Efficient SN2 Reactions in Oxetane Rings; Pseudoenantiomeric Analogues of the Antibiotic Oxetin Tetrahedron: Asymmetry 2004, 15, 2681– 2686 DOI: 10.1016/j.tetasy.2004.07.032
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Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Pérez-Victoria, I.; Claridge, T. D. W.; Fleet, G. W. J.; Jones, J. H. The Synthesis of Oligomers of Oxetane-Based Dipeptide Isosteres Derived from L-Rhamnose or D-Xylose J. Pept. Sci. 2005, 11, 303– 318 DOI: 10.1002/psc.622
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The synthesis of oligomers of oxetane-based dipeptide isosteres derived from L-rhamnose or D-xylose
Johnson, Stephen W.; Jenkinson, Sarah F.; Angus, Donald; Perez-Victoria, Ignacio; Claridge, Timothy D. W.; Fleet, George W. J.; Jones, John H.
Journal of Peptide Science (2005), 11 (6), 303-318CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
Routes to oligomers (dimers, tetramers, hexamers) of five oxetane-based dipeptide isosteres have been established. Me 2,4-anhydro-5-azido-5-deoxy-L-rhamnonate 'monomer' led, by coupling the corresponding carboxylic acid and amine, to a 'dimer'. Reverse-aldol ring-opening occurred on attempted sapon. of the dimer, so all further oligomerization was performed using TBDMS C-3 hydroxyl protection. The silyl protected L-rhamnonate monomer led in turn to the dimer (via the monomer acid and amine), the tetramer (via the dimer acid and amine) and finally the hexamer (via the tetramer acid and dimer amine). In each case the acids were obtained through sapon. of the resp. Me esters and the amines were obtained by hydrogenation of the azides; coupling was TBTU-mediated. Essentially the same strategy was employed on equiv. D-lyxonate, 6-deoxy-L-altronate, 6-deoxy-D-gulonate and D-fuconate dipeptide isosteres to give the resp. dimers, tetramers and hexamers.
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Sakya, S. M.; Strohmeyer, T. W.; Bitha, P.; Lang, S. A., Jr.; Lin, Y.-I. Synthesis and Structure-Activity Relationships of Some Novel Oxetane Carbapenems Bioorg. Med. Chem. Lett. 1997, 7, 1805– 1810 DOI: 10.1016/S0960-894X(97)00280-1
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Leanza, W. J.; Wildonger, K. J.; Miller, T. W.; Christensen, B. G. N-Acetimidoyl- and N-Formimidoylthienamycin Derivatives: Antipseudomonal β-Lactam Antibiotics J. Med. Chem. 1979, 22, 1435– 1436 DOI: 10.1021/jm00198a001
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Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Jones, J. H.; Watkin, D. J.; Fleet, G. W. J. Pseudoenantiomeric Oxetane δ-Amino Acid Scaffolds Derived from L-Rhamnose and D-Xylose: D/L-Alanine-D-Serine and Glycine-L-Serine Dipeptide Isosteres Tetrahedron: Asymmetry 2004, 15, 3263– 3273 DOI: 10.1016/j.tetasy.2004.08.023
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Jenkinson (née Barker), S. F.; Harris, T.; Fleet, G. W. J. Oxetane cis- and trans β-Amino-Acid Scaffolds from D-Xylose by Efficient S_N2 Reactions in Oxetane Rings: Methyl and Hydroxymethyl Analogues of the Antibiotic Oxetin, an Oxetane β-Amino-Acid Tetrahedron: Asymmetry 2004, 15, 2667– 2679 DOI: 10.1016/j.tetasy.2004.07.031
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Knijnenburg, A. D.; Tuin, A. W.; Spalburg, E.; de Neeling, A. J.; Mars-Groenendijk, R. H.; Noort, D.; Otero, J. M.; Llamas-Saiz, A. L.; van Raaij, M. J.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. Exploring the Conformational and Biological Versatility of β-Turn-Modified Gramicidin S by Using Sugar Amino Acid Homologues That Vary in Ring Size Chem. - Eur. J. 2011, 17, 3995– 4004 DOI: 10.1002/chem.201002895
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Exploring the conformational and biological versatility of β-turn-modified gramicidin S by using sugar amino acid homologs that vary in ring size
Knijnenburg, Annemiek D.; Tuin, Adriaan W.; Spalburg, Emile; de Neeling, Albert J.; Mars-Groenendijk, Roos H.; Noort, Daan; Otero, Jose M.; Llamas-Saiz, Antonio L.; van Raaij, Mark J.; van der Marel, Gijs A.; Overkleeft, Herman S.; Overhand, Mark
Chemistry - A European Journal (2011), 17 (14), 3995-4004, S3995/1-S3995/11CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (contg. an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties dets. the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-contg. peptides is solvent dependent. The deriv. contg. the pyranoid SAA is slightly less hydrophobic and displays a diminished hemolytic activity, but has similar antimicrobial properties as GS.
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Claridge, T. D. W.; Lopez-Ortega, B.; Jenkinson, S. F.; Fleet, G. W. J. Secondary Structural Investigations into Homo-Oligomers of δ-2,4-Cis Oxetane Amino Acids Tetrahedron: Asymmetry 2008, 19, 984– 988 DOI: 10.1016/j.tetasy.2008.03.029
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Lopez-Ortega, B.; Jenkinson, S. F.; Claridge, T. D. W.; Fleet, G. W. J. Oxetane Amino Acids: Synthesis of Tetrameric and Hexameric Carbopeptoids Derived from L-Ribo 4-(aminomethyl)-Oxetan-2-Carboxylic Acid Tetrahedron: Asymmetry 2008, 19, 976– 983 DOI: 10.1016/j.tetasy.2008.03.030
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Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus, D.; Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet, G. W. J. 10-Helical Conformations In Oxetane B-Amino Acid Hexamers Tetrahedron Lett. 2001, 42, 4251– 4255 DOI: 10.1016/S0040-4039(01)00661-X
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Johnson, S. W.; Jenkinson (née Barker), S. F.; Pérez-Victoria, I.; Edwards, A. A.; Claridge, T. D. W.; Tranter, G. E.; Fleet, G. W. J.; Jones, J. H. Conformational Studies of Oligomeric Oxetane-Based Dipeptide Isosteres Derived From L-Rhamnose or D-Xylose J. Pept. Sci. 2005, 11, 517– 524 DOI: 10.1002/psc.658
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188
Conformational studies of oligomeric oxetane-based dipeptide isosteres derived from L-rhamnose or D-xylose
Johnson, Stephen W.; Jenkinson, Sarah F.; Perez-Victoria, Ignacio; Edwards, Alison A.; Claridge, Timothy D. W.; Tranter, George E.; Fleet, George W. J.; Jones, John H.
Journal of Peptide Science (2005), 11 (9), 517-524CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
Conformational investigations have been undertaken on oligomers (dimers, tetramers, hexamers) of five closely related oxetane-based dipeptide isosteres. All the oligomers were subjected to a range of studies by NMR, FT-IR and CD spectroscopy. The oligomers derived from Me 2,4-anhydro-5-azido-3-O-tert-butyldimethylsilyl-5-deoxy-L-rhamnonate "monomer" all exhibited evidence of ordered conformations in chloroform and 2,2,2-trifluoroethanol (TFE) soln. 5-Acetamido and N-methylamide derivs. of the L-rhamnonate "monomer", along with a "dimer" lacking silyl protection at C-3, were synthesized to ascertain the role of intramol. interactions. This led to the conclusion that, for the L-rhamnonate oligomers, steric interactions govern the conformational preference obsd. The equivalent silyl-protected D-lyxonate oligomers gave ordered CD spectra in TFE soln., but NMR and FT-IR spectroscopy in chloroform soln. suggested an irregular, non-hydrogen bonded system. The remaining silyl-protected 6-deoxy-L-altronate, 6-deoxy-D-gulonate and D-fuconate oligomers appear to be characterized by their lack of ordered conformation in TFE and chloroform soln.
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Fleet, G. W. J.; Johnson, S. W.; Jones, J. H. Cyclic Oligomers of Oxetane-Based Dipeptide Isosteres Derived from L-Rhamnose J. Pept. Sci. 2006, 12 (8) 559– 561 DOI: 10.1002/psc.759
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Cyclic oligomers of oxetane-based dipeptide isosteres derived from L-rhamnose
Fleet, George W. J.; Johnson, Stephen W.; Jones, John H.
Journal of Peptide Science (2006), 12 (8), 559-561CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
Two new cyclic oligomers, cyclo-tetra-[2,4-anhydro-3-O-tert-butyldimethylsilyl-5-deoxy-L-rhamnonamido-(N→5)] and the corresponding 6-deoxy-D-gulonate cyclic 'tetramer', have been synthesized from linear tetrameric oligomers, using TBTU- and pentafluorophenyl ester-based methodologies, resp. These two compds. constitute a novel class of cyclic oligomers derived from oxetane-based sugar amino acids.
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Sharma, G. V. M; Venkateshwarlu, G.; Katukuri, S.; Ramakrishna, K. V. S.; Sarma, A. V. S. Design and Synthesis of Novel Oxetane β³-Amino Acids and α,β-Peptides Tetrahedron 2015, 71, 2158– 2167 DOI: 10.1016/j.tet.2015.02.039
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191
Chan, L. C.; Cox, B. G. Kinetics of Amide Formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) Couplings J. Org. Chem. 2007, 72, 8863– 8869 DOI: 10.1021/jo701558y
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Kinetics of Amide Formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) Couplings
Chan, Lai C.; Cox, Brian G.
Journal of Organic Chemistry (2007), 72 (23), 8863-8869CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the iso-Pr ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concn. of HOBt, showing that the rate-detg. step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the obsd. rate consts. for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH22+, 6) and the carboxylate group. The obsd. rate consts. fall sharply at high pH, as the fraction of EDCI as EDCIH22+ continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate const., kP, for reaction between the carboxylate group of acid, 3, and EDCIH22+ has a value of kP = 4.1 × 104 M-1 s-1 at 20 °C, some 105 times higher than similar rate consts. measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, dets. the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal arom. amine of 3 to give the diamide 5.
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Pastor-Anglada, M.; Felipe, A.; Casado, F. J. Transport and Mode of Action of Nucleoside Derivatives Used in Chemical and Antiviral Therapies Trends Pharmacol. Sci. 1998, 19, 424– 430 DOI: 10.1016/S0165-6147(98)01253-X
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Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies
Pastor-Anglada, Marcal; Felipe, Antonio; Casado, F. Javier
Trends in Pharmacological Sciences (1998), 19 (10), 424-430CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Science Ltd.)
A review with 50 refs. Nucleoside analogs used in cancer and anti-viral therapies interfere with nucleotide metab. and DNA replication, thus inducing their pharmacol. effects. A long-awaited goal in the understanding of the pharmacol. properties of these mols., that is the mol. characterization of nucleoside plasma-membrane transporters, has been achieved very recently. These carrier proteins are encoded by at least two gene families and new isoforms remain to be identified. Direct demonstration of translocation of these drugs by nucleoside transporters has already been provided and most of them can inhibit natural nucleoside-transport, probably in a competitive manner. The expression of these genes is clearly tissue-specific and might depend on the differentiated status of a cell. This is relevant because the sensitivity of a cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might modulate nucleoside carrier expression. In this article, Marcal Pastor-Anglada, Antonio Felipe and Javier Casado discuss recent studies on the regulation of nucleoside carrier expression and of the mol. determinants of substrate specificity. Better knowledge of these will contribute to an improved design of therapies based on nucleoside derivs.
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Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Nucleoside Analogues and Nucleobases in Cancer Treatment Lancet Oncol. 2002, 3, 415– 424 DOI: 10.1016/S1470-2045(02)00788-X
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Nucleoside analogues and nucleobases in cancer treatment
Galmarini, Carlos M.; Mackey, John R.; Dumontet, Charles
Lancet Oncology (2002), 3 (7), 415-424CODEN: LOANBN; ISSN:1470-2045. (Lancet Publishing Group)
A review. Cytotoxic nucleoside analogs and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. This family of compds. has grown to include a variety of purine and pyrimidine nucleoside derivs. with activity in both solid tumors and malignant disorders of the blood. These agents behave as antimetabolites, compete with physiol. nucleosides, and interact with a large no. of intracellular targets to induce cytotoxicity. Progress has recently been made in the identification and characterization of nucleoside transporters and the enzymes of nucleoside metab. In addn., there is now greater understanding of the mol. mechanisms of anticancer nucleoside activity, which provides opportunities for potentiating their antitumor effects. Strategies to optimize intracellular analog accumulation and to enhance cancer-cell selectivity are proving beneficial in clin. trials.
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Prusoff, W. H. Synthesis and Biological Activities of Iododeoxyuridine, An Analogue Of Thymidine Biochim. Biophys. Acta 1959, 32, 295– 296 DOI: 10.1016/0006-3002(59)90597-9
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Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St Clair, M. H.; Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder, S. 3′-Azido-3′-deoxythymidine (BW A509U): An Antiviral Agent That Inhibits The Infectivity And Cytopathic Effect Of Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus In Vitro Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 7096– 7100 DOI: 10.1073/pnas.82.20.7096
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3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro
Mitsuya, Hiroaki; Weinhold, Kent J.; Furman, Phillip A.; St. Clair, Marty H.; Lehrman, Sandra Nusinoff; Gallo, Robert C.; Bolognesi, Dani; Barry, David W.; Broder, Samuel
Proceedings of the National Academy of Sciences of the United States of America (1985), 82 (20), 7096-100CODEN: PNASA6; ISSN:0027-8424.
The antiviral effects of a thymidine analog, 3'-azido-3'-deoxythymidine (BW A509U)(I) [30516-87-1], which, as a triphosphate, inhibits the reverse transcriptase of human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-assocd. virus (LAV) was detd. This agent blocked the expression of the p24 gag protein of HTLV-III/LAV in H9 cells following exposure to virus. The drug also inhibited the cytopathic effect of HTLV-IIIB (a virus derived from a pool of American patients) and HTLV-III/RF-II (an isolate obtained from a Haitian patient that differs by about 20% in the amino acid sequence of the envelope gene from several isolates of HTLV-III/LAV, including HTLV-IIIB, analyzed so far). 3'-Azido-3'-deoxythymidine also completely blocked viral replication as assessed by reverse transcriptase prodn. in normal human peripheral blood mononuclear cells exposed to HTLV-III. Finally, at concns. of 3'-azido-3'-deoxythymidine that block the in vitro infectively and cytopathic effect of HTLV-IIIB, the in vitro immune functions of normal T cells remain basically intact. These results are relevant to the treatment of AIDS.
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Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.; Zahler, R.; Colonno, R. J. Identification of BMS-200475 as a Potent and Selective Inhibitor of Hepatitus B Virus Antimicrob. Agents Chemother. 1997, 41, 1444– 1448
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Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Steuer, H. M. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus J. Med. Chem. 2010, 53, 7202– 7218 DOI: 10.1021/jm100863x
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Discovery of a β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus
Sofia, Michael J.; Bao, Donghui; Chang, Wonsuk; Du, Jinfa; Nagarathnam, Dhanapalan; Rachakonda, Suguna; Reddy, P. Ganapati; Ross, Bruce S.; Wang, Peiyuan; Zhang, Hai-Ren; Bansal, Shalini; Espiritu, Christine; Keilman, Meg; Lam, Angela M.; Steuer, Holly M. Micolochick; Niu, Congrong; Otto, Michael J.; Furman, Phillip A.
Journal of Medicinal Chemistry (2010), 53 (19), 7202-7218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-Me nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate deriv. of the β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepd. and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixt. 14 was crystd., and an X-ray structure was detd. establishing the phosphoramidate stereochem. as Sp, thus correlating for the first time the stereochem. of a phosphoramidate prodrug with biol. activity. 51 (PSI-7977) was selected as a clin. development candidate.
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De Clercq, E. De. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies For Intervention With HIV Infections J. Med. Chem. 1995, 38, 2491– 2517 DOI: 10.1021/jm00014a001
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Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections
De Clercq, Erik
Journal of Medicinal Chemistry (1995), 38 (14), 2491-517CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review, with 250 refs.
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Gish, R. G.; Clark, M. D.; Kane, S. D.; Shaw, R. E.; Mangahas, M. F.; Baqai, S. Similar Risk of Renal Events Among Patients Treated With Tenofovir or Entecavir for Chronic Hepatitis B Clin. Gastroenterol. Hepatol. 2012, 10, 941– 946 DOI: 10.1016/j.cgh.2012.04.008
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Similar risk of renal events among patients treated with tenofovir or entecavir for chronic hepatitis B
Gish Robert G; Clark Margaret D; Kane Steve D; Shaw Richard E; Mangahas Michael F; Baqai Sumbella
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2012), 10 (8), 941-6; quiz e68 ISSN:.
BACKGROUND & AIMS: Tenofovir is a nucleotide reverse-transcriptase inhibitor approved for treatment of human immunodeficiency virus infection, as well as chronic hepatitis B (CHB). We evaluated nephrotoxicity among patients with CHB treated with tenofovir. METHODS: We performed a community-based, retrospective cohort study of 80 patients with CHB who received tenofovir, alone or in a combination regimen; they were matched for age and sex with 80 CHB patients who received only entecavir. Incidences of serum creatinine (SCr) increase ≥0.2 mg/dL and new SCr levels of 1.5, 2.0, or 2.5 mg/dL were assessed. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min, calculated using the Modification of Diet in Renal Disease or Cockcroft-Gault formula, or who had ≥20% decrease in eGFR were also recorded. RESULTS: More patients given entecavir had increases in SCr ≥2.5 mg/dL (1 vs 6; P = .053), whereas more patients given tenofovir had a new Cockcroft-Gault eGFR of <60 mL/min (15 vs 6; P = .022) and at least 1 dose adjustment (13 vs 4; P = .021). By multivariate analysis, the only significant factors associated with an increase in SCr were a history of organ transplantation (adjusted odds ratio, 6.740; 95% confidence interval, 1.799-28.250; P = .005) and pre-existing renal insufficiency (adjusted odds ratio, 10.960; 95% confidence interval, 2.419-48.850; P = .002). No factors, including therapy assignment, were associated with a new eGFR <60 mL/min. CONCLUSIONS: Markers of renal function indicated that patients who received tenofovir were no more likely to have changes in renal function than patients treated with entecavir. History of transplant and pre-existing renal insufficiency were the only factors independently associated with increases in SCr.
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Chemical Synthesis of Nucleoside Analogues; Merino, P., Ed.; John Wiley & Sons: Hoboken, NJ, 2013; DOI: DOI: 10.1002/9781118498088 .
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Christensen, N. K.; Petersen, M.; Nielsen, P.; Jacobsen, J. P.; Olsen, C. E.; Wengel, J. A Novel Class of Oligonucleotide Analogues Containing 2′-O,3′-C-Linked [3.2.0]Bicycloarabinonucleoside Monomers: Synthesis, Thermal Affinity Studies, and Molecular Modeling J. Am. Chem. Soc. 1998, 120, 5458– 5463 DOI: 10.1021/ja9743598
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Sørensen, M. H.; Nielsen, C.; Nielsen, P. Synthesis of a Bicyclic Analogue of AZT Restricted in an Unusual O4′-Endo Conformation J. Org. Chem. 2001, 66, 4878– 4886 DOI: 10.1021/jo010299j
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Sharma, P. K.; Nielsen, P. New Ruthenium-Based Protocol for Cleavage of Terminal Olefins to Primary Alcohols: Improved Synthesis of a Bicyclic Nucleoside J. Org. Chem. 2004, 69, 5742– 5745 DOI: 10.1021/jo0491861
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Pradeepkumar, P. I.; Chattopadhyaya, J. Oxetane Modified Antisense Oligonucleotides Promote RNase H Cleavage of the Complementary RNA Strand in the Hybrid Duplex as Efficiently as the Native, and Offer Improved Endonuclease Resistance J. Chem. Soc. Perkin Trans. 2 2001, 2074– 2083 DOI: 10.1039/b106281f
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Oxetane modified antisense oligonucleotides promote RNase H cleavage of the complementary RNA strand in the hybrid duplex as efficiently as the native, and offer improved endonuclease resistance
Pradeepkumar, Pushpangadan I.; Chattopadhyaya, Jyoti
Journal of the Chemical Society, Perkin Transactions 2 (2001), (11), 2074-2083CODEN: JCSPGI; ISSN:1472-779X. (Royal Society of Chemistry)
Although the Tm drops ∼6/modification (note: Tm loss is ∼10/mismatch) in the oxetane, [1-(1',3'-O-anhydro-β-D-psicofuranosyl)thymine, T], modified antisense (AON)-RNA heteroduplexes, the relative rates of the complementary RNA cleavage by RNase H remain the same as or comparable to that of the native counterpart. The RNA cleavage in the native hybrid duplex was 68±3% (Tm = 44), whereas it was 64±10% for the single T modified AON-RNA duplex (Tm = 39), 56±9% for the double T modified AON-RNA duplex (Tm = 33) and 60±7% for the triple T modified AON-RNAs (Tm = 26). The oxetane modifications in AON reduce the endonuclease cleavage (DNase 1) significantly. One modification gives ∼2-fold protection and three modifications give ∼4-fold protection compared to that of the native. Introductions of both interior oxetane modifications in conjunction with the 3'-DPPZ (dipyridophenazine) group give the resulting AON-RNA hybrid an RNase H cleavage rate at least the same as that of the native counterpart, which, addnl., gives full stability against both exo- and endonucleases. The conformational transmission of the constrained 3'-endo sugar of the oxetane nucleotide in the AON strand is transmitted up to a stretch of five nucleotides in the heteroduplex as is evident by the RNase H resistance to the cleavage of the complementary RNA strand, thereby showing that this five-nucleotide region most probably takes up a local RNA-RNA type conformation. This is the first report of an antisense oligonucleotide construct which fulfills three important criteria simultaneously: (1) the modified AON promotes the complementary RNA cleavage by RNase H at an efficiency comparable to that of the native counterpart, (2) the modified AON has substantially more endonuclease stability than that of the native AON, and finally, (3) the DPPZ group at the 3'-end provides the expected exonuclease stability. This also shows that the Tm increase of the AON-RNA hybrid duplex is not mandatory for RNase H promoted destruction of the target RNA.
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Pradeepkumar, P. I.; Amirkhanov, N. V.; Chattopadhyaya, J. Antisense Oligonuclotides with Oxetane-Constrained Cytidine Enhance Heteroduplex Stability, and Elicit Satisfactory Rnase H Response as well as Showing Improved Resistance to Both Exo and Endonucleases Org. Biomol. Chem. 2003, 1, 81– 92 DOI: 10.1039/b210163g
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Bogucka, M.; Nauš, P.; Pathmasiri, W.; Barman, J.; Chattopadhyaya, J. Facile Preparation of the Oxetane-Nucleosides Org. Biomol. Chem. 2005, 3, 4362– 4372 DOI: 10.1039/b511406c
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207
Komsta, Z.; Mayes, B.; Moussa, A.; Shelbourne, M.; Stewart, A.; Tyrrell, A. J.; Wallis, L. L.; Weymouth-Wilson, A. C.; Yurek-George, A. Synthesis and Anti-HCV Activity of 1-(1′,3′-O-Anhydro-3′-C-methyl-β-D-psicofuranosyl)uracil Tetrahedron Lett. 2014, 55, 6216– 6219 DOI: 10.1016/j.tetlet.2014.09.069
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Chang, W.; Du, J.; Rachakonda, S.; Ross, B. S.; Convers-Reignier, S.; Yau, W. T.; Pons, J.-F.; Murakami, E.; Bao, H.; Steuer, H. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Synthesis and Anti-HCV Activity of 3′,4′-Oxetane Nucleosides Bioorg. Med. Chem. Lett. 2010, 20, 4539– 4543 DOI: 10.1016/j.bmcl.2010.06.025
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Synthesis and anti-HCV activity of 3',4'-oxetane nucleosides
Chang, Wonsuk; Du, Jinfa; Rachakonda, Suguna; Ross, Bruce S.; Convers-Reignier, Serge; Yau, Wei T.; Pons, Jean-Francois; Murakami, Eisuke; Bao, Haiying; Steuer, Holly Micolochick; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.
Bioorganic & Medicinal Chemistry Letters (2010), 20 (15), 4539-4543CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Hepatitis C virus afflicts approx. 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clin. trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepd. as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as detd. in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivs. were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
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Du, J.; Chun, B.-K; Mosley, R. T.; Bansal, S.; Bao, H.; Espiritu, C.; Lam, A. M.; Murakami, E.; Niu, C.; Steuer, H. M. M.; Furman, P. A.; Sofia, M. J. Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design J. Med. Chem. 2014, 57, 1826– 1835 DOI: 10.1021/jm401224y
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Jonckers, T. H. M.; Vandyck, K.; Vandekerckhove, L.; Hu, L.; Tahri, A.; Van Hoof, S.; Lin, T.-I; Vijgen, L.; Berke, J. M.; Lachau-Durand, S.; Stoops, B.; Leclercq, L.; Fanning, G.; Samuelsson, B.; Nilsson, M.; Rosenquist, Å.; Simmen, K.; Raboisson, P. Nucleotide Prodrugs of 2′-Deoxy-2′-Spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase J. Med. Chem. 2014, 57, 1836– 1844 DOI: 10.1021/jm4015422
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Nucleotide Prodrugs of 2'-Deoxy-2'-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
Jonckers, Tim H. M.; Vandyck, Koen; Vandekerckhove, Leen; Hu, Lili; Tahri, Abdellah; Van Hoof, Steven; Lin, Tse-I.; Vijgen, Leen; Berke, Jan Martin; Lachau-Durand, Sophie; Stoops, Bart; Leclercq, Laurent; Fanning, Gregory; Samuelsson, Bertil; Nilsson, Magnus; Rosenquist, Asa; Simmen, Kenny; Raboisson, Pierre
Journal of Medicinal Chemistry (2014), 57 (5), 1836-1844CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects assocd. with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was obsd. in both rat and human hepatocyte cultures. In addn., after oral dosing of several phosphoramidate derivs. of compd. 21 (I) to rats, substantial hepatic levels of the active triphosphate metabolite were found.
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Sharma, V. K.; Kumar, M.; Sharma, D.; Olsen, C. E.; Prasad, A. K. Chemoenzymatic Synthesis of C-4′-Spiro-Oxetanoribonucleosides J. Org. Chem. 2014, 79, 8516– 8521 DOI: 10.1021/jo501655j
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Ehlinger, E.; Magnus, P. Silicon in Synthesis. 10. The (Trimethylsilyl)allyl Anion: A β-Acyl Anion Equivalent for the Conversion of Aldehydes and Ketones into γ-Lactones J. Am. Chem. Soc. 1980, 102, 5004– 5011 DOI: 10.1021/ja00535a600
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Silicon in synthesis. 10. The (trimethylsilyl)allyl anion: a β-acyl anion equivalent for the conversion of aldehydes and ketones into γ-lactones
Ehlinger, Ed; Magnus, Philip
Journal of the American Chemical Society (1980), 102 (4), 5004-11CODEN: JACSAT; ISSN:0002-7863.
The (trimethylsilyl)allyl anion reacted with a no. of ketones and aldehydes to give adducts RCR1(OH)CH2CH:CHSiMe3; the adducts were epoxidized to provide the corresponding epoxy silanes I. Treatment of the I with MeOH in the presence of boron trifluoride etherate gave lactol Me ethers II, and Jones oxidn. of the lactol ethers gave γ-lactones III.
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Manabe, S.; Nishino, C. Stereochemistry of cis-Clerodane Diterpenes Tetrahedron 1986, 42, 3461– 3470 DOI: 10.1016/S0040-4020(01)87313-0
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Stereochemistry of cis-clerodane diterpenes
Manabe, Shunichi; Nishino, Chikao
Tetrahedron (1986), 42 (13), 3461-70CODEN: TETRAB; ISSN:0040-4020.
To piscicidal solidagolactones IV, V, VII and VIII isolated from Solidago altissima, a nonsteroidal conformation was assigned on the basis of chem. and physicochem. evidence. 13C NMR chem. shifts of Me groups proved useful for detg. stereochem. of the A/B ring junction in clerodanes. For clerodanes having an epoxide, 1H NMR data and the Tori equation were useful for assigning the epoxide configuration. Cremer's puckering parameters were used to express the conformation of the solidagolactones.
214
Paquette, L. A.; Edmondson, S. D.; Monck, N.; Rogers, R. D. Studies Directed toward the Synthesis of the Unusual Antileukemic Diterpene Jatrophatrione. 2. Functionalization of Advanced Polycyclic Precursors to the 9-Epi and 8,9-Dehydro Congeners J. Org. Chem. 1999, 64, 3255– 3265 DOI: 10.1021/jo982526w
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Studies Directed toward the Synthesis of the Unusual Antileukemic Diterpene Jatrophatrione. 2. Functionalization of Advanced Polycyclic Precursors to the 9-Epi and 8,9-Dehydro Congeners
Paquette, Leo A.; Edmondson, Scott D.; Monck, Nathaniel; Rogers, Robin D.
Journal of Organic Chemistry (1999), 64 (9), 3255-3265CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The synthesis of highly functionalized [5.9.5]tricyclic systems closely related to jatrophatrione (I; R = α-H) and 9-epijatrophatrione (I; R = β-H) is described. The first set of expts. provides a route to the conjugated 7-methylene ketones II (R1 = C6H4OMe-4, H), both of which resist migration of the exocyclic double bond to a position internal to the ring. Subsequent dihydroxylation studies define a convenient pathway from III to triketone IV, which has yet to exhibit a tendency to undergo appropriate dehydration at the tertiary carbinol center. The presence of a carbonyl group in ring C was shown not to be contributory to this low reactivity. Finally, a protocol involving formation of a bromo oxetane with subsequent introduction of a C8-C9 double bond and Grob fragmentation has shown promise for arrival at I by making available the diene V.
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Evans, R. D.; Magee, J. W.; Schauble, J. H. Halocyclization of Unsaturated Alcohols and Carboxylic Acids Using Bis(sym-collidine)iodine(I) Perchlorate Synthesis 1988, 1988, 862– 868 DOI: 10.1055/s-1988-27731
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Galatsis, P.; Millan, S. D.; Ferguson, G. Enantioselective Construction of Cyclic Ethers by An Aldol-Cyclization Sequence J. Org. Chem. 1997, 62, 5048– 5056 DOI: 10.1021/jo961904z
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Galatsis, P.; Millan, S. D.; Nechala, P.; Ferguson, G. Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans J. Org. Chem. 1994, 59, 6643– 6651 DOI: 10.1021/jo00101a024
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Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans
Galatsis, Paul; Millan, Scott D.; Nechala, Patrik; Ferguson, George
Journal of Organic Chemistry (1994), 59 (22), 6643-51CODEN: JOCEAH; ISSN:0022-3263.
The application of a tandem deconjugative aldol-cyclization sequence for the construction of substituted tetrahydrofurans was examd. The aldol condensation of alkenoates proceeded with alkylation at the α-position to generate homoallylic alc. moieties. These compds. could be induced to cyclize under the influence of iodine via an endo mode. The stereoselectivity for the cyclization occurred in good to excellent fashion. X-ray crystal structure anal. of three of the tetrahydrofurans established unambiguously the product stereochem. This was used to propose a transition structure for the cyclization which correctly predicts the obsd. product stereochem. By this method, virtually all the possible stereoisomers for the substituted tetrahydrofurans can be constructed by judicious choice of aldol product and/or olefin geometry.
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Rofoo, M.; Roux, M.-C.; Rousseau, G. Preparation of Oxetanes by Silicon-Directed 4-Exo Trig Electrophilic Cyclisations of Homoallylic Alcohols Tetrahedron Lett. 2001, 42, 2481– 2484 DOI: 10.1016/S0040-4039(01)00227-1
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Brown, W. L.; Fallis, A. G. Intramolecular Rearrangements: Epimerization of Bicyclic Vinyl Tertiary Alcohols via a [2,3] Sulfoxide Sigmatropic Rearrangement Can. J. Chem. 1987, 65, 1828– 1832 DOI: 10.1139/v87-307
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Arjona, O.; de la Pradilla, R. F.; Plumet, J.; Viso, A. Regioselective Electrophilic Additions to 2-Oxygenated-7-xabicyclo[2.2.1]hept-5-enes: A Simple Entry into the 4,7-Dioxatricyclo[3.2.1.0^3,6]octaneskeleton Tetrahedron 1989, 45, 4565– 4578 DOI: 10.1016/S0040-4020(01)89091-8
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Arjona, O.; de la Pradilla, R. F.; Plumet, J.; Viso, A. Temperature-Controlled Synthesis of 4,7-Dioxatricyclo[3.2.1.0^3,6]octane Derivatives J. Org. Chem. 1992, 57, 772– 774 DOI: 10.1021/jo00028a074
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Homsi, F.; Rousseau, G. 4-Endo-Trig Cyclization Processes Using Bis(collidine)bromine(I) Hexafluorophosphate as Reagent: Preparation of 2-Oxetanones, 2-Azetidinones, and Oxetanes J. Org. Chem. 1999, 64, 81– 85 DOI: 10.1021/jo9810361
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4-Endo-Trig Cyclization Processes Using Bis(collidine)bromine(I) Hexafluorophosphate as Reagent: Preparation of 2-Oxetanones, 2-Azetidinones, and Oxetanes
Homsi, Fadi; Rousseau, Gerard
Journal of Organic Chemistry (1999), 64 (1), 81-85CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Reaction in methylene chloride of bis(collidine)bromine hexafluorophosphate with α,β-unsatd. acids and α,β-unsatd. N-sulfonamides was found to lead diastereospecifically to the corresponding 2-oxetanones and 2-azetidinones in moderate yields (23-60%), by an almost unknown 4-endo cyclization. This process allow the synthesis of these interesting classes of products in one step from common substrates. Similarly, the reaction of cinnamic alcs. led, by the same cyclization procedure, to oxetanes (20-36%); the presence of a gem-di-Me group in α of the alc. function appeared beneficial.
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Albert, S.; Robin, S.; Rousseau, G. Preparation of Oxetanes by 4-Endo Trig Electrophilic Cyclisations of Cinnamic Alcohols Tetrahedron Lett. 2001, 42, 2477– 2479 DOI: 10.1016/S0040-4039(01)00226-X
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Willand-Charnley, R.; Puffer, B. W.; Dussault, P. H. Oxacycle Synthesis via Intramolecular Reaction of Carbanions and Peroxides J. Am. Chem. Soc. 2014, 136, 5821– 5823 DOI: 10.1021/ja5026276
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Oxacycle Synthesis via Intramolecular Reaction of Carbanions and Peroxides
Willand-Charnley, Rachel; Puffer, Benjamin W.; Dussault, Patrick H.
Journal of the American Chemical Society (2014), 136 (16), 5821-5823CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The intramol. reaction of dialkyl peroxides with carbanions, generated via chemoselective metal-heteroatom exchange or deprotonation, provides a new approach to cyclic ethers. Applied in tandem with C-C bond formation, the strategy enables a one-step annelation to form spirocyclic oxacycles. E.g., in presence of KOCMe3 in THF, PhCO(CH2)4OOCMe3 underwent cyclization to give 81% THF deriv. (I).
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Thijs, L.; Cillissen, P. J. M.; Zwanenburg, B. An Efficient Synthesis of Oxetanones from α,β-Epoxy Diazomethyl Ketones Tetrahedron 1992, 48, 9985– 9990 DOI: 10.1016/S0040-4020(01)92288-4
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Ye, L.; He, W.; Zhang, L. Gold-Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from Readily Available Propargylic Alcohols J. Am. Chem. Soc. 2010, 132, 8550– 8551 DOI: 10.1021/ja1033952
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Gold-Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from Readily Available Propargylic Alcohols
Ye, Longwu; He, Weimin; Zhang, Liming
Journal of the American Chemical Society (2010), 132 (25), 8550-8551CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A general soln. for the synthesis of various oxetan-3-ones, e.g. I, has been developed. This reaction uses readily available propargylic alcs. as substrates and proceeds without the exclusion of moisture or air ("open flask"). Notably, oxetan-3-one, a highly valuable substrate for drug discovery, can be prepd. in one step from propargyl alc. in a fairly good yield. The facile formation of the strained oxetane ring provides strong support for the intermediacy of α-oxo gold carbenes. This safe and efficient generation of gold carbenes via intermol. alkyne oxidn. offers a potentially general entry into α-oxo metal carbene chem. without using hazardous diazo ketones.
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Craig, D.; Munasinghe, V. R. N. Stereoselective Template-Directed C-Glycosidation. Synthesis of Bicyclic Ketooxetanes via Intramolecular Cyclization Reactions of (2-Pyridylthio)Glycosidic Silyl Enol Ethers J. Chem. Soc., Chem. Commun. 1993, 901– 903 DOI: 10.1039/c39930000901
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Mordini, A.; Bindi, S.; Pecchi, S.; Degl’Innocenti, A.; Reginato, G.; Serci, A. Different Pathways in the Base-Promoted Isomerization of Benzyl Oxiranyl Ethers J. Org. Chem. 1996, 61, 4374– 4378 DOI: 10.1021/jo960226d
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Thurner, A.; Faigl, F.; Mordini, A.; Bigi, A.; Reginato, G.; Töke, L. A New Base Promoted Rearrangement of (E)-1-Benzyloxy-2,3-Epoxyalkanes Tetrahedron 1998, 54, 11597– 11602 DOI: 10.1016/S0040-4020(98)00684-X
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Thurner, A.; Faigl, F.; Töke, L.; Mordini, A.; Valacchi, M.; Reginato, G.; Czira, G. Useful Base Promoted Elaborations of Oxiranyl Ethers Tetrahedron 2001, 57, 8173– 8180 DOI: 10.1016/S0040-4020(01)00790-6
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Useful base promoted elaborations of oxiranyl ethers
Thurner, A.; Faigl, F.; Toke, L.; Mordini, A.; Valacchi, M.; Reginato, G.; Czira, G.
Tetrahedron (2001), 57 (38), 8173-8180CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
Functionalized oxiranyl ethers can be regio- and stereoselectively converted into hydroxy oxetanes or cis-diols by treatment with organometallic bases. These two rearrangements can be conveniently carried out either using different reaction conditions starting from the oxirane or in two consecutive steps from the oxirane via the oxetane.
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Mordini, A.; Bindi, S.; Pecchi, S.; Capperucci, A.; Degl’Innocent, A.; Reginato, G. A Selective and General Access to Trisubstituted Oxetanes J. Org. Chem. 1996, 61, 4466– 4468 DOI: 10.1021/jo9604595
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Mordini, A.; Valacchi, M.; Nardi, C.; Bindi, S.; Poli, G.; Reginato, G. A Selective Access to Amino Hydroxy Oxetanes J. Org. Chem. 1997, 62, 8557– 8559 DOI: 10.1021/jo9708607
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Mordini, A.; Bindi, S.; Capperucci, A.; Nistri, D.; Reginato, G.; Valacchi, M. Stereoselective Access to Hydroxy Oxetanes and Tetrahydrooxepines through Isomerization of Oxiranyl Ethers J. Org. Chem. 2001, 66, 3201– 3205 DOI: 10.1021/jo0005924
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Stereoselective Access to Hydroxy Oxetanes and Tetrahydrooxepines through Isomerization of Oxiranyl Ethers
Mordini, Alessandro; Bindi, Simona; Capperucci, Antonella; Nistri, Daniele; Reginato, Gianna; Valacchi, Michela
Journal of Organic Chemistry (2001), 66 (9), 3201-3205CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Substituted trans-oxetanemethanols I (R = BuCH2, Me3CSi(Me)2OCH2; R1 = Ph, HC≡C) and cis-substituted tetrahydrooxepines II (R = H, BuCH2, Me3CSi(Me)2OCH2; R1 = H2C:CH) are prepd. regioselectively by lithiation of substituted glycidyl ethers III with lithium bases derived from either butyllithium or lithium diisopropylamide and potassium tert-butoxide. E.g., III (R = BuCH2; R1 = H2C:CH) was added to a THF soln. of hexane-free butyllithium and potassium tert-butoxide (prepd. at -78°) and stirred for 15 h at -50°; after quenching and workup, I (R = BuCH2; R1 = H2C:CH) was obtained in 65% isolated yield as a 98:2 mixt. of regioisomers (with the tetrahydrooxepine II) and as a 98:2 mixt. of stereoisomers. The regiochem. of nucleophilic cyclization depends upon the substitution next to the glycidyl ether oxygen; when the pendant group is either a Ph or ethynyl group, the cyclization gives oxetanemethanol derivs. selectively, while when the pendant group is a vinyl group, tetrahydrooxepine derivs. are obtained as the sole products. Superbase-promoted isomerization of oxiranyl ethers thus allows convenient access to oxetane and tetrahydrooxepane derivs with high regio- and stereoselectivities.
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Faigl, F.; Thurner, A.; Tárkányi, G.; Kovári, J.; Mordini, A. Resolution and Enantioselective Rearrangements of Amino Group-Containing Oxiranyl Ethers Tetrahedron: Asymmetry 2002, 13, 59– 68 DOI: 10.1016/S0957-4166(02)00051-4
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Studies on the total synthesis of oxetanocin. I. The first synthesis of a nucleoside having oxetanosyl-N-glycoside
Niitsuma, Setsuko; Ichikawa, Yuichiro; Kato, Kuniki; Takita, Tomohisa
Tetrahedron Letters (1987), 28 (34), 3967-70CODEN: TELEAY; ISSN:0040-4039.
The first synthesis of 9-(2-oxetanyl)adenine I, a key intermediate for the synthesis of the novel nucleoside oxetanocin (II), was achieved via cyclization between the allyloxy carbanion and the epoxy group in III.
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Niitsuma, S.; Kato, K.; Takita, T. Studies on the Total Synthesis of Oxetanocin; II. Total Synthesis of Oxetanocin Tetrahedron Lett. 1987, 28, 4713– 4714 DOI: 10.1016/S0040-4039(00)96606-1
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Studies on the total synthesis of oxetanocin. II. Total synthesis of oxetanocin
Niitsuma, Setsuko; Ichikawa, Yuichiro; Kato, Kuniki; Takita, Tomohisa
Tetrahedron Letters (1987), 28 (40), 4713-14CODEN: TELEAY; ISSN:0040-4039.
Oxetanyladenine I, whose prepn. has been previously reported, was converted into oxetanocin (II) in 5 steps.
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Maegawa, T.; Otake, K.; Hirosawa, K.; Goto, A.; Fujioka, H. Method for the Efficient Synthesis of Highly-Substituted Oxetan- and Azetidin-, Dihydrofuran- and Pyrrolidin-3-Ones and Its Application to the Synthesis of (±)-Pseudodeflectusin Org. Lett. 2012, 14, 4798– 4801 DOI: 10.1021/ol302096j
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246
Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A. 2-(Aryl-sulfonyl)oxetanes as Designer 3-Dimensional Fragments for Fragment Screening: Synthesis and Strategies for Functionalisation Chem. Commun. 2014, 50, 5203– 5205 DOI: 10.1039/C3CC46450D
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2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation
Morgan, Kate F.; Hollingsworth, Ian A.; Bull, James A.
Chemical Communications (Cambridge, United Kingdom) (2014), 50 (40), 5203-5205CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
2-Sulfonyl-oxetanes were prepd., affording non-planar structures with desirable physicochem. properties for fragment based drug discovery. The oxetane motif was formed by an intramol. C-C bond formation. The fragments were further functionalized via organometallic intermediates at the intact oxetane and arom. rings.
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Morgan, K. F.; Doran, R.; Croft, R. A.; Hollingsworth, I. A.; Bull, J. A. 2-Sulfinyl Oxetanes: Synthesis, Stability and Reactivity Synlett 2016, 27, 106– 110 DOI: 10.1055/s-0035-1560588
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248
Davis, O. A.; Bull, J. A. Recent Advances in the Synthesis of 2-Substituted Oxetanes Synlett 2015, 26, 1283– 1288 DOI: 10.1055/s-0034-1380412
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Recent Advances in the Synthesis of 2-Substituted Oxetanes
Davis, Owen A.; Bull, James A.
Synlett (2015), 26 (10), 1283-1288CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
A review. Recent interest in oxetanes in medicinal chem. and as synthetic intermediates has led to the development of a no. of methods for the synthesis of more functionalized and highly substituted oxetane derivs. Here we review cyclization approaches for the prepn. of 2-substituted oxetanes. Methods involving C-O bond formation, as well as recently developed C-C bond forming cyclization strategies are highlighted.
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Davis, O. A.; Croft, R. A.; Bull, J. A. Synthesis of Diversely Functionalised 2,2-Disubstituted Oxetanes: Fragment Motifs in New Chemical Space Chem. Commun. 2015, 51, 15446– 15449 DOI: 10.1039/C5CC05740J
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Synthesis of diversely functionalized 2,2-disubstituted oxetanes: fragment motifs in new chemical space
Davis, Owen A.; Croft, Rosemary A.; Bull, James A.
Chemical Communications (Cambridge, United Kingdom) (2015), 51 (84), 15446-15449CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
The synthesis of diversely functionalized oxetane derivs., e.g., I in new chem. space, was achieved via rhodium-catalyzed O-H insertion and C-C bond forming cyclization.
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D’Auria, M.; Racioppi, R. Concepts of Stereoselective Photochemistry and a Case Study: The Paterno-Buchi Reaction Curr. Org. Chem. 2009, 13, 939– 954 DOI: 10.2174/138527209788452126
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250
Concepts of stereoselective photochemistry and a case study: the Paterno-Buchi reaction
D'Auria, Maurizio; Racioppi, Rocco
Current Organic Chemistry (2009), 13 (9), 939-954CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
A review. The main methods reported in literature to obtain stereoselective photochem. reaction is reviewed. The most important approached attempted to obtain stereoselective photochem. reaction are as follows. The use of diastereoselective photochem. reactions. The use of mols. with prevented mobility, and this approach can be obtained by the following. Introducing chiral auxiliary. Introducing chiral mols. in the reaction mixt. able to give complexes with a reduced mobility. Performing the reaction in organized media such as zeolites or cyclodextrins. Performing the reaction on single crystal. Performing the reaction on single crystals of mols. able to give crystal in chiral space group. Finally performing the reaction in solid phase on inclusion complexes of the substrate with chiral mols. Using chiral solvents and chiral light. Using chiral photosensitizers. The case of the diastereoselective Paterno-Buchi reaction on furan derivs. is also discussed.
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Eftekhari-Sis, B.; Zirak, M. Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles Chem. Rev. 2015, 115, 151– 264 DOI: 10.1021/cr5004216
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251
Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles
Eftekhari-Sis, Bagher; Zirak, Maryam
Chemical Reviews (Washington, DC, United States) (2015), 115 (1), 151-264CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
There is no expanded citation for this reference.
252
Bach, T. The Paterno-Büchi Reaction of 3-Heteroatom-Substituted Alkenes as a Stereoselective Entry to Polyfunctional Cyclic and Acyclic Molecules Liebigs Ann. Chem. 1997, 1997, 1627– 1634 DOI: 10.1002/jlac.199719970803
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253
Griesbeck, A. G.; Abe, M.; Bondock, S. Selectivity Control in Electron Spin Inversion Processes: Regio- and Stereochemistry of Paternò-Büchi Photocycloadditions as a Powerful Tool for Mapping Intersystem Crossing Processes Acc. Chem. Res. 2004, 37, 919– 928 DOI: 10.1021/ar040081u
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254
Abe, M.; Kawakami, T.; Ohata, S.; Nozaki, K.; Nojima, M. Mechanism of Stereo- and Regioselectivity in the Paternò-Büchi Reaction of Furan Derivatives with Aromatic Carbonyl Compounds: Importance of the Conformational Distribution in the Intermediary Triplet 1,4-Diradicals J. Am. Chem. Soc. 2004, 126, 2838– 2846 DOI: 10.1021/ja039491o
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255
Palmer, I. J.; Ragazos, I. N.; Bernardi, F.; Olivucci, M.; Robb, M. A. An MC-SCF Study of the (Photochemical) Paterno-Buchi Reaction J. Am. Chem. Soc. 1994, 116, 2121– 2132 DOI: 10.1021/ja00084a058
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255
An MC-SCF Study of the (Photochemical) Paterno-Buechi Reaction
Palmer, Ian J.; Ragazos, Ioannis N.; Bernardi, Fernando; Olivucci, Massimo; Robb, Michael A.
Journal of the American Chemical Society (1994), 116 (5), 2121-32CODEN: JACSAT; ISSN:0002-7863.
An MC-SCF/6-31G* study of the singlet and triplet Paterno-Buechi reaction (for the model system formaldehyde and ethylene) is presented. In addn. to the computation of the relevant min. and transition structures, the Born-Oppenheimer violation regions, where a fast decay from the singlet excited state (S1) to the ground state (S0) surface takes place, have been fully characterized by locating and optimizing the structure of two different S0/S1 conical intersections. The photochem. mechanisms of oxetane formation via carbon-carbon (C-C) and carbon-oxygen (C-O) attacks have both been investigated. For the C-C attack the singlet mechanism can be concerted as the decay to the ground state takes place in a point where the C-C bond is fully formed. Thus, starting from this decay point, the system can evolve directly to oxetane or produce a C-C bonded transient diradical intermediate. The C-O attack leads to a nonconcerted path only. In this case, the excited-state branch of the reaction coordinate terminates in a conical intersection point at a C-O distance of 1.77 Å before the diradical is fully formed. Thus, the system can evolve back to the reactant or produce a C-O bonded transient diradical intermediate that is isolated by very small barriers to fragmentation or ring-closure to oxetane. While the diradical structures corresponding to the two modes of attack differ in energy by only 8 kcal mol-1, the S1 to S0 decay point for C-C attack lies 33 kcal mol-1 below the corresponding point for C-O attack. The triplet diradicals have energies and geometries that are very similar to the singlets. Thus the authors predict that intersystem crossing from triplet to singlet will lead to the same diradical ground-state pathways that can be entered via singlet photochem.
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Paterno-Büchi Reaction. In Comprehensive Organic Name Reactions and Reagents; Wang, Z., Ed.; John Wiley and Sons: 2010; pp 2126– 2130; DOI: DOI: 10.1002/9780470638859 .
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257
Bach, T.; Jödicke, K.; Kather, K.; Fröhlich, R. 1,3-Allylic Strain as a Control Element in the Paternò–Büchi Reaction of Chiral Silyl Enol Ethers: Synthesis of Diastereomerically Pure Oxetanes Containing Four Contiguous Stereogenic Centers J. Am. Chem. Soc. 1997, 119, 2437– 2445 DOI: 10.1021/ja963827v
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Bach, T.; Kather, K. Hydroxyl-Directed Reductive Cleavage of 3-Oxetanols as an Entry to Diastereomerically Pure 1,2-Diols J. Org. Chem. 1996, 61, 3900– 3901 DOI: 10.1021/jo952235c
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Bach, T. N-Acyl Enamines in the Paternò–Büchi Reaction: Stereoselective Preparation of 1,2-Amino Alcohols by C–C Bond Formation Angew. Chem., Int. Ed. Engl. 1996, 35, 884– 886 DOI: 10.1002/anie.199608841
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N-Acyl enamines in the Paterno-Buechi reaction: stereoselective preparation of 1,2-amino alcohols by C-C bond formation
Bach, Thorsten
Angewandte Chemie, International Edition in English (1996), 35 (8), 884-886CODEN: ACIEAY; ISSN:0570-0833. (VCH)
The Paterno-Buechi reaction of N-ethenylamides with benzaldehyde gave cis-N-(2-phenyl-3-oxetanyl)acetamides or cis-(2-phenyl-3-oxetanyl)carbamic acid esters. For example, the cyclization of 2,3-dihydro-1H-pyrrole-1-carboxylic acid Me ester (I) gave the fused oxazolidine II which upon hydrolytic ring cleavage gave cis-3-hydroxy-2-(phenylmethyl)-1-pyrrolidinecarboxylic acid Me ester.
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Bach, T.; Brummerhop, H. Unprecedented Facial Diastereoselectivity in the Paternò–Büchi Reaction of - A Chiral Dihydropyrrole - A Short Total Synthesis of (+)-Preussin Angew. Chem., Int. Ed. 1998, 37, 3400– 3402 DOI: 10.1002/(SICI)1521-3773(19981231)37:24<3400::AID-ANIE3400>3.0.CO;2-3
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261
Bach, T.; Schröder, J. Photocycloaddition of N-Acyl Enamines to Aldehydes and Its Application to the Synthesis of Diastereomerically Pure 1,2-Amino Alcohols J. Org. Chem. 1999, 64, 1265– 1273 DOI: 10.1021/jo9819988
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Photocycloaddition of N-Acyl Enamines to Aldehydes and Its Application to the Synthesis of Diastereomerically Pure 1,2-Amino Alcohols
Bach, Thorsten; Schroeder, Juergen
Journal of Organic Chemistry (1999), 64 (4), 1265-1273CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The regio- and stereoselective synthesis of protected cis-aminooxetanes is reported. The oxetanes were obtained by the photocycloaddn. of aliph. and arom. aldehydes to the corresponding enamides or enecarbamates. The enamine derivs. used in the Paterno-Buechi reaction were either com. available or prepd. from the corresponding acetaldehyde imines by acylation. The oxetane formation proceeded with good-to-excellent simple diastereoselectivity for arom. aldehydes (56-82% yield) and moderate selectivity for aliph. aldehydes (46-55% yield). The cis-3-aminooxetanes are precursors for syn- and anti-1,2-amino alcs. The relative configuration established in the photochem. step was retained upon nucleophilic ring opening between the oxygen atom and carbon atom C-4. By this means, syn-1,2-amino alcs. were available in good yields. In contrast, some N-Boc-protected cis-3-aminooxetanes were transformed into anti-1,2-amino alcs. Upon treatment with trifluoroacetic acid, they underwent an intramol. nucleophilic substitution at the carbon atom C-2 of the oxetane and oxazolidinones were formed. Because the substitution occurs with inversion of configuration, anti-1,2-amino alcs., e.g., ephedrine, are accessible.
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Bach, T.; Schröder, J. The Paternò–Büchi Reaction of α-Alkyl-Substituted Enecarbamates and Benzaldehyde Synthesis 2001, 112, 1117– 1124 DOI: 10.1055/s-2001-15075
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Bach, T.; Brummerhop, H.; Harms, K. The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò–Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles Chem. - Eur. J. 2000, 6, 3838– 3848 DOI: 10.1002/1521-3765(20001016)6:20<3838::AID-CHEM3838>3.3.CO;2-T
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The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buechi reactions of chiral 2-substituted 2,3-dihydropyrroles
Bach, Thorsten; Brummerhop, Harm; Harms, Klaus
Chemistry - A European Journal (2000), 6 (20), 3838-3848CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
The N-alkoxycarbonyl substituted 2,3-dihydropyrroles are converted to 2-benzyl-3-pyrrolidinols by the Paterno-Buechi reaction followed by hydrogenolysis. Since the addn. of the photoexcited benzaldehyde at the unsatd. heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paterno-Buechi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin was conducted, which yielded the target compd. in a total yield of 11% over nine steps starting from L-pyroglutaminol.
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Vogt, F.; Jödicke, K.; Schröder, J.; Bach, T. Paternò-Büchi Reactions of Silyl Enol Ethers and Enamides Synthesis 2009, 4268– 4273 DOI: 10.1055/s-0029-1217095
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Paterno-Buechi reactions of silyl enol ethers and enamides
Vogt, Florian; Joedicke, Kai; Schroeder, Juergen; Bach, Thorsten
Synthesis (2009), (24), 4268-4273CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
3-(Silyloxy)oxetanes are obtained by irradiating mixts. of arom. aldehydes and silyl enol ethers in benzene as the solvent. The reactions occur with high simple diastereoselectivity and, when R1 is chiral, with high facial diastereoselectivity. Under similar conditions, but in acetonitrile rather than benzene as the preferred solvent, the Paterno-Buechi reaction of N-acyl enamines (enamides) gives the corresponding protected 3-aminooxetanes. The cis-products are obtained with significant simple diastereoselectivity.
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Bach, T. The Paternò-Büchi Reaction of N-Acyl Enamines and Aldehydes – The Development of a New Synthetic Method and its Application to Total Synthesis and Molecular Recognition Studies Synlett 2000, 2000 (12) 1699– 1707 DOI: 10.1055/s-2000-8668
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Griesbeck, A. G.; Franke, M.; Neudörfl, J.; Kotaka, H. Photocycloaddition of Aromatic and Aliphatic Aldehydes to Isoxazoles: Cycloaddition Reactivity and Stability Studies Beilstein J. Org. Chem. 2011, 7, 127– 134 DOI: 10.3762/bjoc.7.18
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Photocycloaddition of aromatic and aliphatic aldehydes to isoxazoles: cycloaddition reactivity and stability studies
Griesbeck, Axel G.; Franke, Marco; Neudoerfl, Joerg; Kotaka, Hidehiro
Beilstein Journal of Organic Chemistry (2011), 7 (), 127-134, No. 18CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
The first photocycloaddns. of arom. and aliph. aldehydes to methylated isoxazoles are reported. The reactions lead solely to the exo-adducts with high regio- and diastereoselectivities. E.g., photocycloaddn of 3,4,5-trimethylisoxazole with PhCHO gave 50% exo-oxetane I. Ring methylation of the isoxazole substrates is crucial for high conversions and product stability. The 6-arylated bicyclic oxetanes, e.g. I, were characterized by X-ray structure analyses and showed the highest thermal stabilities. All oxetanes formed from isoxazoles were highly acid-sensitive and also thermally unstable. Cleavage to the original substrates is dominant and the isoxazole-derived oxetanes show type T photochromism.
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Huang, C.; Yu, H.; Miao, Z.; Zhou, J.; Wang, S.; Fun, H.-K.; Xu, J.; Zhang, Y. Facile Synthesis of Spiroisoquinolines Based on Photocycloaddition of Isoquinoline-1,3,4-Trione with Oxazoles Org. Biomol. Chem. 2011, 9, 3629– 3631 DOI: 10.1039/c1ob05143a
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Bach, T.; Bergmann, H.; Harms, K. High Facial Diastereoselectivity in the Photocycloaddition of a Chiral Aromatic Aldehyde and an Enamide Induced by Intermolecular Hydrogen Bonding J. Am. Chem. Soc. 1999, 121, 10650– 10651 DOI: 10.1021/ja992209m
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High Facial Diastereoselectivity in the Photocycloaddition of a Chiral Aromatic Aldehyde and an Enamide Induced by Intermolecular Hydrogen Bonding
Bach, Thorsten; Bergmann, Hermann; Harms, Klaus
Journal of the American Chemical Society (1999), 121 (45), 10650-10651CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Chiral arom. aldehydes I [R = H, Me] were prepd. from the Me esters and 3-HOC6H4CHO and underwent photochem. cycloaddn. with 3,4-dihydro-1H-2-pyridinone (II) to give the oxaazabicyclohexanones III after cleavage of the chiral auxiliary. I [R = H], which forms a 1:1 complex with II, gives (-)-III with high stereoselectivity, whereas the reaction with I [R = Me] is not stereoselective.
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Bach, T.; Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K. The [2+2]-Photocycloaddition of Aromatic Aldehydes and Ketones to 3,4-Dihydro-2-Pyridones: Regioselectivity, Diastereoselectivity, and Reductive Ring Opening of the Product Oxetanes Chem. - Eur. J. 2001, 7, 4512– 4521 DOI: 10.1002/1521-3765(20011015)7:20<4512::AID-CHEM4512>3.0.CO;2-H
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The [2+2]-photocycloaddition of aromatic aldehydes and ketones to 3,4-dihydro-2-pyridones: regioselectivity, diastereoselectivity, and reductive ring opening of the product oxetanes
Bach, Thorsten; Bergmann, Hermann; Brummerhop, Harm; Lewis, Warren; Harms, Klaus
Chemistry - A European Journal (2001), 7 (20), 4512-4521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
3,4-Dihydro-2(1H)-pyridinone derivs. were prepd. and evaluated with respect to their use as alkene components in stereoselective Paterno-Buchi reactions. 3,4-Dihydro-2(1H)-pyridinone was shown to be a versatile synthetic building block that reacted with various photoexcited arom. carbonyl compds. (benzaldehyde, benzophenone, acetophenone, Me phenylglyoxylate, 3-pivaloyloxybenzaldehyde) with high regioselectivity and diastereoselectivity (51-63% yield). The products can be subjected to hydrogenolysis, opening a new and efficient route for the synthesis of 2-arylmethyl-3-piperidinols. As examples, oxetanes thus prepd. were hydrogenolytically cleaved. These oxetanes included (1R,6S,8R)-rel-8-phenyl-7-oxa-2-azabicyclo[4.2.0]octan-3-one and (1R,6S)-rel-8,8-diphenyl-7-oxa-2-azabicyclo[4.2.0]octan-3-one. The ability of 3,4-dihydro-2(1H)-pyridinone to bind to a chiral lactam host through two hydrogen bonds was used favorably to differentiate the enantiotopic faces of its double bond. The reactant prepd. and used in this case was (+)-(1R,5S,7S)-1,5,7-trimethyl-2-oxo-3-Azabicyclo[3.3.1]nonane-7-carboxylic acid 3-formylphenyl ester. In the photocycloaddn. to a chiral aldehyde, which was conducted at - 10°C in toluene, a high facial diastereoselectivity (>90% de, 56% yield) was recorded. The stereo-selectivity results from a 1:1 assocn. of 3,4-dihydro-2(1H)-pyridinone to the aldehyde. Other 4-substituted dihydropyridones, 3,4-dihydro-4-methyl-2(1H)-pyridinone, 3,4-dihydro-4-(1-methylethyl)-2(1H)-pyridinone, and 3,4-dihydro-4-phenyl-2(1H)-pyridinone, were found to be less suited for potential use in photochem. The yields and facial diastereoselectivities recorded in their photocycloaddn. to benzophenone remained low.
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Nehrings, A.; Scharf, H.-D.; Runsink, J. Photochemical Synthesis of an L-Erythrose Building Block and Its Use in the Preparation of Methyl 2,3,O-Isopropylidene-β-L-Apio-L-Furanoside Angew. Chem., Int. Ed. Engl. 1985, 24, 877– 878 DOI: 10.1002/anie.198508771
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271
Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. Hydroxy-Directed Regio- and Diastereoselective [2+2] Photocycloaddition (Paternò–Büchi Reaction) of Benzophenone to Chiral Allylic Alcohols J. Am. Chem. Soc. 2000, 122, 2958– 2959 DOI: 10.1021/ja994279z
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Hambalek, R.; Just, G. A Short Synthesis of (±)-Oxetanocin Tetrahedron Lett. 1990, 31, 5445– 5448 DOI: 10.1016/S0040-4039(00)97868-7
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A short synthesis of (±)-oxetanocin
Hambalek, Robert; Just, George
Tetrahedron Letters (1990), 31 (38), 5445-8CODEN: TELEAY; ISSN:0040-4039.
The photoadduct I of 2-methylfuran and propionyloxyacetaldehyde was transformed in a one-pot reaction to oxetane II, which gave oxetanocin and epioxetanocin.
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Iriondo-Alberdi, J.; Perea-Buceta, J. E.; Greaney, M. F. A Paternò–Büchi Approach to the Synthesis of Merrilactone A Org. Lett. 2005, 7, 3969– 3971 DOI: 10.1021/ol0514496
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274
Xue, J.; Zhang, Y.; Wu, T.; Fun, H.-K.; Xu, J.-H. Photoinduced [2+2] Cycloadditions (the Paternò–Büchi reaction) of 1H-1-Acetylindole-2,3-dione with Alkenes J. Chem. Soc. Perkin Trans. 1 2001, 183– 191 DOI: 10.1039/b005576j
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275
Matsumura, K.; Mori, T.; Inoue, Y. Wavelength Control of Diastereodifferentiating Paternò–Büchi Reaction of Chiral Cyanobenzoates with Diphenylethene through Direct versus Charge-Transfer Excitation J. Am. Chem. Soc. 2009, 131, 17076– 17077 DOI: 10.1021/ja907156j
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Matsumura, K.; Mori, T.; Inoue, Y. Solvent and Temperature Effects on Diastereodifferentiating Paternò–Büchi Reaction of Chiral Alkyl Cyanobenzoates with Diphenylethene upon Direct versus Charge-Transfer Excitation J. Org. Chem. 2010, 75, 5461– 5469 DOI: 10.1021/jo101332x
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277
D’Annibale, A.; D’Auria, M.; Prati, F.; Romagnoli, C.; Stoia, S.; Racioppi, R.; Viggiani, L. Paternò-Büchi Reaction versus Hydrogen Abstraction in the Photochemical Reactivity of Alkenyl Boronates with Benzophenone Tetrahedron 2013, 69, 3782– 3795 DOI: 10.1016/j.tet.2013.03.068
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278
Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Flow Photochemistry: Old Light through New Windows Beilstein J. Org. Chem. 2012, 8, 2025– 2052 DOI: 10.3762/bjoc.8.229
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Flow photochemistry: Old light through new windows
Knowles, Jonathan P.; Elliott, Luke D.; Booker-Milburn, Kevin I.
Beilstein Journal of Organic Chemistry (2012), 8 (), 2025-2052, No. 229CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
A review. Synthetic photochem. carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilized technique in general org. synthesis. Recent developments in flow photochem. have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in org. photochem., allowing a comparison of the various reactor types to be made.
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Fukuyama, T.; Hino, Y.; Kamata, N.; Ryu, I. Quick Execution of [2+2] Type Photochemical Cycloaddition Reaction by Continuous Flow System Using a Glass-Made Microreactor Chem. Lett. 2004, 33, 1430– 1431 DOI: 10.1246/cl.2004.1430
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280
Fukuyama, T.; Kajihara, Y.; Hino, Y.; Ryu, I. Continuous Microflow [2+2] Photocycloaddition Reactions Using Energy-Saving Compact Light Sources J. Flow Chem. 2011, 1, 40– 45 DOI: 10.1556/jfchem.2011.00007
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Continuous microflow [2 + 2] photocycloaddition reactions using energy-saving compact light sources
Fukuyama, Takahide; Kajihara, Yoshito; Hino, Yoshiko; Ryu, Ilhyong
Journal of Flow Chemistry (2011), 1 (), 40-45CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
Photocycloaddn. of cyclohexenones with vinyl acetates or vinyl ethers and the Paterno-Buchi reaction were carried out using photomicroreactors in combination with compact light sources such as low-power black lights and UV LEDs. The obsd. high efficiency holds promise as an energy-saving protocol for photoinduced [2 + 2] cycloaddn. reactions.
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Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B. Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity Chem. - Eur. J. 2014, 20, 15226– 15232 DOI: 10.1002/chem.201404347
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Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity
Elliott, Luke D.; Knowles, Jonathan P.; Koovits, Paul J.; Maskill, Katie G.; Ralph, Michael J.; Lejeune, Guillaume; Edwards, Lee J.; Robinson, Richard I.; Clemens, Ian R.; Cox, Brian; Pascoe, David D.; Koch, Guido; Eberle, Martin; Berry, Malcolm B.; Booker-Milburn, Kevin I.
Chemistry - A European Journal (2014), 20 (46), 15226-15232CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The use of flow photochem. and its apparent superiority over batch has been reported by a no. of groups in recent years. To rigorously det. whether flow does indeed have an advantage over batch, a broad range of synthetic photochem. transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an av. productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chem. was demonstrated in the scale(coating process)-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.
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Terao, K.; Nishiyama, Y.; Kakiuchi, K. Highly Efficient Asymmetric Paternò–Büchi Reaction in a Microcapillary Reactor Utilizing Slug Flow J. Flow Chem. 2014, 4, 35– 39 DOI: 10.1556/JFC-D-13-00035
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282
Highly efficient asymmetric Paterno-Buchi reaction in a microcapillary reactor utilizing slug flow
Terao, Kimitada; Nishiyama, Yasuhiro; Kakiuchi, Kiyomi
Journal of Flow Chemistry (2014), 4 (1), 35-39, 5CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
An asym. Paterno-Buchi-type photoreaction between 2,3-dimethyl-2-butene and benzoylformic acid ester with a chiral menthyl auxiliary was studied in a continuous-flow microcapillary reactor. The fluorinated ethylene propylene microcapillary reactor using normal one-layer flow mode gave oxetane products with better efficiency than the batch system. In addn., the slug flow mode in microcapillary reactor using inactive reagent, N2 gas or H2O, improved the reaction efficiency dramatically because of synergistic light dispersion, stirring and thin layer film effects. The reaction efficiencies under each condition were discussed as energy efficiencies calcd. from reactors parameters.
283
Mikami, K.; Aikawa, K.; Aida, J. Fragment-Based Reaction Discovery of Non-Ene-Type Carbon-Carbon Bond-Forming Reactions: Catalytic Asymmetric Oxetane Synthesis by Screening Olefinic Reactants without Allylic Hydrogen Synlett 2011, 2011, 2719– 2724 DOI: 10.1055/s-0031-1289540
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284
Aikawa, K.; Hioki, Y.; Shimizu, N.; Mikami, K. Catalytic Asymmetric Synthesis of Stable Oxetenes via Lewis Acid-Promoted [2+2] Cycloaddition J. Am. Chem. Soc. 2011, 133, 20092– 20095 DOI: 10.1021/ja2085299
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284
Catalytic Asymmetric Synthesis of Stable Oxetenes via Lewis Acid-Promoted [2 + 2] Cycloaddition
Aikawa, Kohsuke; Hioki, Yuta; Shimizu, Natsumi; Mikami, Koichi
Journal of the American Chemical Society (2011), 133 (50), 20092-20095CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A highly enantioselective and atom-economical [2 + 2] cycloaddn. of various alkynes with trifluoropyruvate using a dicationic (S)-BINAP-Pd catalyst has been established. This is the first enantioselective synthesis of stable oxetene derivs., e.g., I, whose structure has been clarified by X-ray anal. This catalytic process offers a practical synthetic method for oxetene derivs. (catalyst loading: up to 0.1 mol %), which can serve as novel chiral building blocks for pharmaceuticals and agrochems. and can also be transformed into a variety of enantiomerically enriched CF3-substituted compds. with high stereoselectivity.
285
Aikawa, K.; Hioki, Y.; Mikami, K. Highly Enantioselective Alkynylation of Trifluoropyruvate with Alkynylsilanes Catalyzed by the BINAP–Pd Complex: Access to α-Trifluoromethyl-Substituted Tertiary Alcohols Org. Lett. 2010, 12, 5716– 5719 DOI: 10.1021/ol102541s
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285
Highly Enantioselective Alkynylation of Trifluoropyruvate with Alkynylsilanes Catalyzed by the BINAP-Pd Complex: Access to α-Trifluoromethyl-Substituted Tertiary Alcohols
Aikawa, Kohsuke; Hioki, Yuta; Mikami, Ko-ichi
Organic Letters (2010), 12 (24), 5716-5719CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
A highly enantioselective alkynylation catalyzed by the dicationic (S)-BINAP-Pd complex with a variety of alkynylsilanes and trifluoropyruvate is described. The catalytic reaction is applicable to highly enantioselective addn. of polyyne to trifluoropyruvate to construct α-trifluoromethyl-substituted tertiary alcs., e.g., I as enantiomerically enriched forms. The alkynyl products can be converted into a chiral allene bearing a trifluoromethyl group.
286
Baum, K.; Berkowitz, P. T.; Grakauskas, V.; Archibald, T. G. Synthesis of Electron-Deficient Oxetanes. 3-Azidooxetane, 3-Nitrooxetane, and 3,3-Dinitrooxetane J. Org. Chem. 1983, 48, 2953– 2956 DOI: 10.1021/jo00166a003
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Synthesis of electron-deficient oxetanes. 3-Azidooxetane, 3-nitrooxetane, and 3,3-dinitrooxetane
Baum, Kurt; Berkowitz, Phillip T.; Grakauskas, Vytautas; Archibald, Thomas G.
Journal of Organic Chemistry (1983), 48 (18), 2953-6CODEN: JOCEAH; ISSN:0022-3263.
Oxetane I (R = OH, R1 = H) was prepd. by addn. of HOAc to epichlorohydrin, protection of the resulting alc. as an acetal, hydrolysis, ring closure, and removal of the protecting group. I (R = N3, R1 = H) was prepd. from I (R = 4-MeC6H4SO3, R1 = H) and NaN3. Redn. of the azide with Ph3P or H gave I (R = NH2, R1 = H), and oxidn. of the amine with 3-ClC6H4C(O)OOH gave I (R = NO2, R1 = H). Oxidative nitration or reaction with C(NO2)4 gave I (R = R1 = NO2). I (R = N3, R1 = H; R = R1 = NO2) were polymd. with Lewis acids.
287
Wojtowicz, J. A.; Polak, R. J. 3-Substituted Oxetanes J. Org. Chem. 1973, 38, 2061– 2066 DOI: 10.1021/jo00951a020
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3-Substituted oxetanes
Wojtowicz, J. A.; Polak, R. J.
Journal of Organic Chemistry (1973), 38 (11), 2061-6CODEN: JOCEAH; ISSN:0022-3263.
3-Allyloxyoxetane was isomerized with tert-BuOK to give 85-90% 3-propenoxyoxetane (I) (96% cis). I was cleaved by acid to produce 84% 3-oxetanol. Oxetanone is formed either by oxidn. of oxetanol with chromic oxide-pyridine complex or by heating oxetyl tosylate in Me2SO. Heating oxetyl tosylate above 150° with alkali halides in triethylene glycol gave 75-85% 3-halooxetanes. A lower yield (10-20%) of 3-chlorooxetane was obtained when SOCl2 was reacted with 3-oxetanol. Reaction of iodooxetane with Et2NH at 200° gave 3-dimethylaminooxetane. Oxetyl acetate was prepd. in 84% yield by transesterification of oxetanol with allyl acetate. Transesterification of oxetanol with Et acrylate gave a low yield of oxetyl acrylate; the main product was Et 3-(3-oxetoxy)propionate. The acetate and acrylate esters were also prepd. by acylation of oxetanol.
288
Estrada, A. A.; Chan, B. K.; Baker-Glenn, C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chen, H.; Dominguez, S. L.; Dotson, J.; Drummond, J. Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors J. Med. Chem. 2014, 57, 921– 936 DOI: 10.1021/jm401654j
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Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
Estrada, Anthony A.; Chan, Bryan K.; Baker-Glenn, Charles; Beresford, Alan; Burdick, Daniel J.; Chambers, Mark; Chen, Huifen; Dominguez, Sara L.; Dotson, Jennafer; Drummond, Jason; Flagella, Michael; Fuji, Reina; Gill, Andrew; Halladay, Jason; Harris, Seth F.; Heffron, Timothy P.; Kleinheinz, Tracy; Lee, Donna W.; Pichon, Claire E. Le; Liu, Xingrong; Lyssikatos, Joseph P.; Medhurst, Andrew D.; Moffat, John G.; Nash, Kevin; Scearce-Levie, Kimberly; Sheng, Zejuan; Shore, Daniel G.; Wong, Susan; Zhang, Shuo; Zhang, Xiaolin; Zhu, Haitao; Sweeney, Zachary K.
Journal of Medicinal Chemistry (2014), 57 (3), 921-936CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small mol. inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition. Using previously reported aminopyrazole I as a lead mol., we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 and GNE-9605 as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclin. efficacy and safety studies.
289
Wang, Z.; Chen, Z.; Sun, J. Catalytic Enantioselective Intermolecular Desymmetrization of 3-Substituted Oxetanes Angew. Chem., Int. Ed. 2013, 52, 6685– 6688 DOI: 10.1002/anie.201300188
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Angewandte Chemie, International Edition (2013), 52 (26), 6685-6688CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Under optimized reaction conditions, the synthesis of the target compds. was achieved using (11aR)-10,11,12,13-tetrahydro-5-hydroxy-3,7-di(9-phenanthrenyl)diindeno[7,1-de:1',7'-fg][1,3,2]dioxaphosphocin 5-oxide (chiral cyclic phosphate) as a catalyst. A stereoselective ring opening reaction of 3-(phenyl)oxetane (I) with 2(3H)-benzothiazolethione [thiol, 2-(mercapto)benzothiazole] gave a chiral mercapto alc. (II).
290
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Man, A.; Petrus, A.; Sterrenburg, J.-G.; Raaijmakers, H. C. A.; Kaptein, A.; Oubrie, A. A.; Rewinkel, J.; Bernardus, M.; Jans, C. G. J. M.; Wijkmans, J. C. H. M.; Barf, T. A.; Gao, X.; Boga, S. B.; Yao, X.; Zhu, H. Y.; Cooper, A. B.; Kim, R. M. (MSD Oss BV). (4-(5-Membered Fused Pyridinyl)benzamides as BTK-Inhibitors. European Patent EP 2548877 A1, 2013.
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Kim, R. M.; Liu, J.; Gao, X.; Boga, S. B.; Guiadeen, D.; Kozlowski, J. A.; Yu, W.; Anand, R.; Yu, Y.; Selyutin, O. B.; Gao, Y.-D.; Wu, H.; Liu, S.; Yang, C.; Wang, H. (Merck Sharp & Dohme Corp.). BTK Inhibitors. U.S. Patent US 2014206681 A1, 2014.
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Luo, G.; Chen, L.; Dubowchik, G. M.; Jacutin-Porte, S. E.; Vrudhula, V. M.; Pan, S.; Sivaprakasam, P.; Macor, J. E. (Bristol-Myers Squibb Co.). GSK-3 Inhibitors. International Patent WO 201569594 A1, 2015.
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Heuer, T. S.; Oslob, J. D.; Mcdowell, R. S.; Johnson, R.; Yang, H.; Evanchik, M.; Zaharia, C. A.; Cai, H.; Hu, L. W.; Duke, G.; Ohol, Y.; O’Farrell, M. (3-V Biosciences Inc.). Heterocyclic Modulators of Lipid Synthesis and Combinations Thereof. International Patent WO 201595767 A1, 2015.
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Burger, M.; Ding, Y.; Han, W.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Smith, A. R.; Tamez, Jr., V.; Tanner, H.; Wan, L., (Novartis AG). Tetrasubstituted Cyclohexyl Compounds as Kinase Inhibitors. U.S. Patent US 2012225061 A1, 2012.
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Burger, M.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Tamez, Jr., V.; Tanner, H.; Wan, L. (Novartis AG). N-(3-Pyridyl)biarylamides as Kinase Inhibitors. International Patent WO 2014033631 A1, 2014.
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Aliagas-Martin, I.; Crawford, J.; Lee, W.; Mathieu, S.; Rudolph, J. (F. Hoffmann-La Roche AG). Serine/threonine PAK1 Inhibitors. International Patent WO 2013026914 A1, 2013.
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Estrada, A. A.; Shore, D. G.; Blackwood, E.; Chen, Y.-H.; Deshmukh, G.; Ding, X.; DiPasquale, A. G.; Epler, J. A.; Friedman, L. S.; Koehler, M. F. T. Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR) J. Med. Chem. 2013, 56, 3090– 3101 DOI: 10.1021/jm400194n
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Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)
Estrada, Anthony A.; Shore, Daniel G.; Blackwood, Elizabeth; Chen, Yung-Hsiang; Deshmukh, Gauri; Ding, Xiao; DiPasquale, Antonio G.; Epler, Jennifer A.; Friedman, Lori S.; Koehler, Michael F. T.; Liu, Lichuan; Malek, Shiva; Nonomiya, Jim; Ortwine, Daniel F.; Pei, Zhonghua; Sideris, Steve; St-Jean, Frederic; Trinh, Lan; Truong, Tom; Lyssikatos, Joseph P.
Journal of Medicinal Chemistry (2013), 56 (7), 3090-3101CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clin. candidate I (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small mol. inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly obsd. with the THQ scaffold, maintain or improve aq. soly. and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of II (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.
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Bowers, S.; Truong, A. P.; Ye, M.; Aubele, D. L.; Sealy, J. M.; Neitz, R. J.; Hom, R. K.; Chan, W.; Dappen, M. S.; Galemmo, R. A. Design and Synthesis of Highly Selective, Orally Active Polo-like Kinase-2 (Plk-2) Inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 2743– 2749 DOI: 10.1016/j.bmcl.2013.02.065
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Kinoshita, K.; Ono, Y.; Emura, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Tanaka, S.; Morikami, K.; Tsukaguchi, T. Discovery of Novel Tetracyclic Compounds as Anaplastic Lymphoma Kinase Inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 3788– 3793 DOI: 10.1016/j.bmcl.2011.04.020
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Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors
Kinoshita, Kazutomo; Ono, Yoshiyuki; Emura, Takashi; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Tanaka, Shota; Morikami, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, Nobuhiro
Bioorganic & Medicinal Chemistry Letters (2011), 21 (12), 3788-3793CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivs. as potent ALK inhibitors. Among them, compd. 27 showed strong cytotoxicity against KARPAS-299 with an IC50 value of 21 nM and significant antitumor efficacy in ALK fusion-pos. blood and solid cancer xenograft models in mice without body wt. loss.
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Kinoshita, K.; Kobayashi, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Hattori, K.; Miyagi, T. 9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors J. Med. Chem. 2011, 54, 6286– 6294 DOI: 10.1021/jm200652u
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9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors
Kinoshita, Kazutomo; Kobayashi, Takamitsu; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Hara, Sousuke; Ohwada, Jun; Hattori, Kazuo; Miyagi, Takuho; Hong, Woo-Sang; Park, Min-Jeong; Takanashi, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, Nobuhiro
Journal of Medicinal Chemistry (2011), 54 (18), 6286-6294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E0 region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compd. 13d (I) showed highly selective and potent inhibitory activity against ALK with an IC50 value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC50 value of 12.8 nM. The compd. also displayed significant antitumor efficacy in an established ALK fusion gene-pos. anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body wt. loss.
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Song, Z.; Yang, Y.; Liu, Z.; Peng, X.; Guo, J.; Yang, X.; Wu, K.; Ai, J.; Ding, J.; Geng, M.; Zhang, A. Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases J. Med. Chem. 2015, 58, 197– 211 DOI: 10.1021/jm5005144
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Phillips, D. P.; Gao, W.; Yang, Y.; Zhang, G.; Lerario, I. K.; Lau, T. L.; Jiang, J.; Wang, X.; Nguyen, D. G.; Bhat, B. G. Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy J. Med. Chem. 2014, 57, 3263– 3282 DOI: 10.1021/jm401731q
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350
Hamzik, P. J.; Brubaker, J. D. Reactions of Oxetan-3-tert-Butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes Org. Lett. 2010, 12, 1116– 1119 DOI: 10.1021/ol100119e
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Reactions of Oxetan-3-tert-butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes
Hamzik, Philip J.; Brubaker, Jason D.
Organic Letters (2010), 12 (5), 1116-1119CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The oxetane ring is useful in drug discovery as a bioisostere for both the geminal di-Me group and the carbonyl group. A convenient, straightforward approach to access structurally diverse 3-aminooxetanes through the reactivity of oxetan-3-tert-butylsulfinimine and the corresponding sulfinylaziridine is described. E.g., 1,2-addn. of oxetan-3-tert-butylsulfinimine (I) with PhLi, generated from BuLi and PhBr, gave 91% 3-aminooxetane II.
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Jung, H. H.; Buesking, A. W.; Ellman, J. A. Highly Functional Group Compatible Rh-Catalyzed Addition of Arylboroxines to Activated N-tert-Butanesulfinyl Ketimines Org. Lett. 2011, 13, 3912– 3915 DOI: 10.1021/ol201438k
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351
Highly Functional Group Compatible Rh-Catalyzed Addition of Arylboroxines to Activated N-tert-Butanesulfinyl Ketimines
Jung, Hyung Hoon; Buesking, Andrew W.; Ellman, Jonathan A.
Organic Letters (2011), 13 (15), 3912-3915CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The rhodium-catalyzed addn. of readily accessible arylboroxines to N-tert-butanesulfinyl ketimines derived from oxetan-3-one, N-Boc-azetidin-3-one, and isatins proceeds in high yields with excellent functional group compatibility to yield amino oxetanes, amino azetidines, and aminooxindoles tertiary carbinamines, e.g., I. Moreover, high diastereoselectivities are obsd. for the addns. to the N-sulfinyl ketimines derived from isatins.
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Brady, P. B.; Carreira, E. M. Addition of Trifluoroborates to Oxetanyl N,O-Acetals: Entry into Spiro and Fused Saturated Heterocycles Org. Lett. 2015, 17, 3350– 3353 DOI: 10.1021/acs.orglett.5b01607
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Addition of Trifluoroborates to Oxetanyl N,O-Acetals: Entry into Spiro and Fused Saturated Heterocycles
Brady, Patrick B.; Carreira, Erick M.
Organic Letters (2015), 17 (13), 3350-3353CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
N,O-Acetals derived from 3-oxetanone and 1,2-amino alcs. such as I underwent addn. reactions with alkynyl-, allyl-, allenyl-, and vinylpotassium trifluoroborates such as RC≡CBF3-K+ [R = H, Ph, 4-ClC6H4, 4-MeOC6H4, 3-FC6H4, Me3Si, cyclohexyl, Cl(CH2)3, TBDMSO(CH2)3, PhCH2CH2] to give substituted oxetanamines such as II (R = H, Ph, PhCH2CH2). The oxetanamines underwent ring expansion reactions to give morpholines and fused morpholines such as III and IV [R1 = H, Ph, 4-ClC6H4, Me3Si, cyclohexyl, Cl(CH2)3]. IV (R1 = H, Ph, 4-ClC6H4, Me3Si, cyclohexyl) underwent gold-catalyzed hydroalkoxylation to yield spirofuranbenzooxazines V as the major products. The structures of a hydroxyphenyl (chloropentynyl)oxetanamine and of V (R = 4-ClC6H4) were detd. by X-ray crystallog.
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Laporte, R.; Prunier, A.; Pfund, E.; Roy, V.; Agrofoglio, L. A.; Lequeux, T. Synthesis of Fluorine-Containing 3,3-Disubstituted Oxetanes and Alkylidene Oxetanes Eur. J. Org. Chem. 2015, 2015 (14) 3121– 3128 DOI: 10.1002/ejoc.201500172
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Hirsch, A. K. H.; Alphey, M. S.; Lauw, S.; Seet, M.; Barandun, L.; Eisenreich, W.; Rohdich, F.; Hunter, W. N.; Bacher, A.; Diederich, F. Inhibitors of the kinase IspE: Structure-activity Relationships and Co-crystal Structure Analysis Org. Biomol. Chem. 2008, 6, 2719– 2730 DOI: 10.1039/b804375b
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355
Phelan, J. P.; Patel, E. J.; Ellman, J. A. Catalytic Enantioselective Addition of Thioacids to Trisubstituted Nitroalkenes Angew. Chem., Int. Ed. 2014, 53, 11329– 11332 DOI: 10.1002/anie.201406971
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Catalytic Enantioselective Addition of Thioacids to Trisubstituted Nitroalkenes
Phelan, James P.; Patel, Evan J.; Ellman, Jonathan A.
Angewandte Chemie, International Edition (2014), 53 (42), 11329-11332CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first example of a catalytic enantioselective addn. to and nitronate protonation of trisubstituted nitroalkenes R1R2C:CR3NO2 [R1 = R2 = Me; R1R2 = CH2OCH2, CH2NBocCH2, CH2CH2OCH2CH2, (CH2)5; R3 = Me, Et, i-Pr, PhCH2, MeO2CCH2CH2] to produce highly enantioenriched products R4C(O)SCR1R2CHR3NO2 (R4 = Me, Ph) with a tetrasubstituted carbon is reported. Thioacids R4C(O)SH added in excellent yields and with high enantioselectivities to both activated and unactivated nitroalkenes. The 1,2-nitrothioacetate products can be readily converted in two steps to biomedically relevant 1,2-aminosulfonic acids without loss of enantiopurity.
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Phelan, J. P.; Ellman, J. A. Catalytic Enantioselective Addition of Pyrazol-5-Ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst Adv. Synth. Catal. 2016, 358, 1713– 1718 DOI: 10.1002/adsc.201600110
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356
Catalytic Enantioselective Addition of Pyrazol-5-ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst
Phelan, James P.; Ellman, Jonathan A.
Advanced Synthesis & Catalysis (2016), 358 (11), 1713-1718CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first example of enantioselective nitronate protonation following Michael addn. of a carbon nucleophile to an α,β,β-trisubstituted nitroalkene is reported. An N-sulfinylurea catalyst was employed to catalyze the addn. of a variety of 3-substituted pyrazol-5-one nucleophiles to trisubstituted nitroalkenes incorporating an oxetane or azetidine ring at the β-position. The nitroalkane-pyrazolone adducts I (R1 = t-Bu, cyclohexyl, 2,6-Me2C6H3; R2 = H, Me, Et, i-Pr, Ph, (CH2)2OMe; R3 = Et, Me, PhCH2, (CH2)2CO2Me; X = O, N-Boc, N-Cbz, N-Ts) were obtained with good yield and enantioselectivity. Furthermore, the Michael addn. products can be reduced to the corresponding enantioenriched amines with minimal loss of enantiomeric purity.
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McLaughlin, M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M. Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry Org. Lett. 2014, 16, 4070– 4073 DOI: 10.1021/ol501590n
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Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry
McLaughlin, Martin; Yazaki, Ryo; Fessard, Thomas C.; Carreira, Erick M.
Organic Letters (2014), 16 (16), 4070-4073CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.
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Powell, N. H.; Clarkson, G. J.; Notman, R.; Raubo, P.; Martin, N. G.; Shipman, M. Synthesis and Structure of Oxetane Containing Tripeptide Motifs Chem. Commun. 2014, 50, 8797– 8800 DOI: 10.1039/C4CC03507K
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Synthesis and structure of oxetane containing tripeptide motifs
Powell, Nicola H.; Clarkson, Guy J.; Notman, Rebecca; Raubo, Piotr; Martin, Nathaniel G.; Shipman, Michael
Chemical Communications (Cambridge, United Kingdom) (2014), 50 (63), 8797-8800CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A new class of peptidomimetic is reported in which one of the amide C:O bonds of the peptide backbone is replaced by an oxetane ring. They are synthesized by conjugate addn. of various α-amino esters to a 3-(nitromethylene)oxetane, redn. of the nitro group and further coupling with N-Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and mol. dynamics simulations.
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Beadle, J. D.; Powell, N. H.; Raubo, P.; Clarkson, G. J.; Shipman, M. Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework Synlett 2016, 27, 169– 172 DOI: 10.1055/s-0035-1560593
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360
Monleón, A.; Glaus, F.; Vergura, S.; Jørgensen, K. A. Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds Angew. Chem., Int. Ed. 2016, 55, 2478– 2482 DOI: 10.1002/anie.201510731
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Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds
Monleon, Alicia; Glaus, Florian; Vergura, Stefania; Jorgensen, Karl Anker
Angewandte Chemie, International Edition (2016), 55 (7), 2478-2482CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first catalytic enantioselective cycloaddn. reaction to α,β,β-trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodol. provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms, e. g., I, in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and -azetidines. Addnl., the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane.
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Beasley, B. O.; Clarkson, G. J.; Shipman, M. Passerini Reactions for the Efficient Synthesis of 3,3-Disubstituted Oxetanes Tetrahedron Lett. 2012, 53, 2951– 2953 DOI: 10.1016/j.tetlet.2012.03.065
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362
Beasley, B. O.; Alli-Balogun, A.; Clarkson, G. J.; Shipman, M. Pictet–Spengler Reactions of Oxetan-3-ones and Related Heterocycles Tetrahedron Lett. 2014, 55, 541– 543 DOI: 10.1016/j.tetlet.2013.11.077
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363
Nassoy, A.-C.; Raubo, P.; Harrity, J. P. A. Synthesis and Cycloaddition Chemistry of Oxetanyl-Substituted Sydnones Tetrahedron Lett. 2013, 54, 3094– 3096 DOI: 10.1016/j.tetlet.2013.03.139
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364
Vo, C.-V. T.; Mikutis, G.; Bode, J. W. SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines—An Alternative to Cross-Coupling with Saturated Heterocycles Angew. Chem., Int. Ed. 2013, 52, 1705– 1708 DOI: 10.1002/anie.201208064
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SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines-An Alternative to Cross-Coupling with Saturated Heterocycles
Vo, Cam-Van T.; Mikutis, Gediminas; Bode, Jeffrey W.
Angewandte Chemie, International Edition (2013), 52 (6), 1705-1708CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
We disclose SnAP reagents for the facile conversion of aldehydes into N-unprotected 3-thiomorpholines. This strategy has the potential to be a general approach to installing satd. heterocycles using aldehydes as a synthetic handle. Its successful execution relies on the use of radical chem. to overcome a long-standing challenge in org. synthesis: C-C bond-forming addn. to unactivated primary imines.
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Siau, W.-Y.; Bode, J. W. One-Step Synthesis of Saturated Spirocyclic N-Heterocycles with Stannyl Amine Protocol (SnAP) Reagents and Ketones J. Am. Chem. Soc. 2014, 136, 17726– 17729 DOI: 10.1021/ja511232b
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One-Step Synthesis of Saturated Spirocyclic N-Heterocycles with Stannyl Amine Protocol (SnAP) Reagents and Ketones
Siau, Woon-Yew; Bode, Jeffrey W.
Journal of the American Chemical Society (2014), 136 (51), 17726-17729CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The combination of cyclic ketones and stannyl amine protocol (SnAP) reagents affords satd., spirocyclic N-heterocycles under operationally simple reaction conditions. The resulting, N-unprotected spirocyclic amines are in great demand as scaffolds for drug discovery and development. The union of SnAP reagents and acyclic trifluoromethyl ketones yields α-CF3 morpholines and piperazines.
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Dobi, Z.; Holczbauer, T.; Soós, T. Strain-Driven Direct Cross-Aldol and -Ketol Reactions of Four-Membered Heterocyclic Ketones Org. Lett. 2015, 17, 2634– 2637 DOI: 10.1021/acs.orglett.5b01002
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367
González-Bobes, F.; Fu, G. C. Amino Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with Arylboronic Acids J. Am. Chem. Soc. 2006, 128, 5360– 5361 DOI: 10.1021/ja0613761
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367
Amino Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with Arylboronic Acids
Gonzalez-Bobes, Francisco; Fu, Gregory C.
Journal of the American Chemical Society (2006), 128 (16), 5360-5361CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Suzuki cross-coupling reactions of an unprecedented array of un-activated primary and secondary alkyl halides (including challenging alkyl chlorides) can be accomplished through the use of nickel/amino alc.-based catalysts. Both the nickel pre-catalyst and the amino alcs. (prolinol or trans-2-aminocyclohexanol) are com. available and air-stable. In view of the remarkable diversity of amino alcs. that are readily accessible, this discovery may open the door to the rapid development of versatile catalysts for a wide range of cross-coupling processes.
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Zhang, X.; Yang, C. Alkylations of Arylboronic Acids including Difluoroethylation/Trifluoroethylation via Nickel-Catalyzed Suzuki Cross-Coupling Reaction Adv. Synth. Catal. 2015, 357, 2721– 2727 DOI: 10.1002/adsc.201500346
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368
Alkylations of Arylboronic Acids including Difluoroethylation/Trifluoroethylation via Nickel-Catalyzed Suzuki Cross-Coupling Reaction
Zhang, Xiaofei; Yang, Chunhao
Advanced Synthesis & Catalysis (2015), 357 (12), 2721-2727CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
An efficient alkylation method of functionalized alkyl halides under mild nickel-catalyzed C(sp3) - C(sp2) Suzuki cross-coupling conditions was described. The features of this approach are excellent functional group compatibility, low cost nickel catalyst, and the use of a mild base. This is also the first successful example of the nickel-catalyzed direct 2,2-difluoroethylation or 2,2,2-trifluoroethylation of aryl-/heteroarylboronic acids.
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Duncton, M. A. J.; Estiarte, M. A.; Johnson, R. J.; Cox, M.; O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. Preparation of Heteroaryloxetanes and Heteroarylazetidines by Use of a Minisci Reaction J. Org. Chem. 2009, 74, 6354– 6357 DOI: 10.1021/jo9010624
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Preparation of Heteroaryloxetanes and Heteroarylazetidines by Use of a Minisci Reaction
Duncton, Matthew A. J.; Estiarte, M. Angels; Johnson, Russell J.; Cox, Matthew; O'Mahony, Donogh J. R.; Edwards, William T.; Kelly, Michael G.
Journal of Organic Chemistry (2009), 74 (16), 6354-6357CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroarom. bases was achieved by using a radical addn. method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetidine into heteroarom. systems that have found important uses in the drug discovery industry, such as the marketed EGFR inhibitor gefitinib, a quinolinecarbonitrile Src tyrosine kinase inhibitor, and the antimalarial hydroquinine.
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Presset, M.; Fleury-Brégeot, N.; Oehlrich, D.; Rombouts, F.; Molander, G. A. Synthesis and Minisci Reactions of Organotrifluoroborato Building Blocks J. Org. Chem. 2013, 78, 4615– 4619 DOI: 10.1021/jo4005519
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Synthesis and Minisci Reactions of Organotrifluoroborato Building Blocks
Presset, Marc; Fleury-Bregeot, Nicolas; Oehlrich, Daniel; Rombouts, Frederik; Molander, Gary A.
Journal of Organic Chemistry (2013), 78 (9), 4615-4619CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Copper-catalyzed borylation of a variety of org. halides with bis(pinacolato)diboron allows the prepn. of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-contg. building blocks, including those contg. piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are reported for select examples.
371
Molander, G. A.; Traister, K. M.; O’Neill, B. T. Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and Heteroaryl Bromides J. Org. Chem. 2014, 79, 5771– 5780 DOI: 10.1021/jo500905m
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Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and Heteroaryl Bromides
Molander, Gary A.; Traister, Kaitlin M.; O'Neill, Brian T.
Journal of Organic Chemistry (2014), 79 (12), 5771-5780CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Reductive cross-coupling allows the direct C-C bond formation between two org. halides without the need for preformation of an organometallic reagent. A method has been developed for the reductive cross-coupling of nonarom., heterocyclic bromides with aryl or heteroaryl bromides. The developed conditions use an air-stable Ni(II) source in the presence of a diamine ligand and a metal reductant to allow late-stage incorporation of satd. heterocyclic rings onto aryl halides in a functional-group tolerant manner. E.g., in presence of NiCl2.(glyme), 1,10-phenanthroline, 4-ethylpyridine, NaBF4, and Mn in MeOH, cross-coupling of 3-bromotetrahydrofuran and 4-BrC6H4COMe gave 54% I.
372
Bhonde, V. R.; O’Neill, B. T.; Buchwald, S. L. An Improved System for the Aqueous Lipshutz-Negishi Cross-Coupling of Alkyl Halides with Aryl Electrophiles Angew. Chem., Int. Ed. 2016, 55, 1849– 1853 DOI: 10.1002/anie.201509341
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372
An improved system for the aqueous Lipshutz-Negishi cross-coupling of alkyl halides with aryl electrophiles
Bhonde, Vasudev R.; O'Neill, Brian T.; Buchwald, Stephen L.
Angewandte Chemie, International Edition (2016), 55 (5), 1849-1853CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.
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Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids J. Org. Chem. 2014, 79, 328– 338 DOI: 10.1021/jo402526z
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Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids
Allwood, Daniel M.; Blakemore, David C.; Brown, Alan D.; Ley, Steven V.
Journal of Organic Chemistry (2014), 79 (1), 328-338CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The coupling of arom. moieties with satd. heterocyclic partners is currently an area of significant interest for the pharmaceutical industry. Herein, we present a procedure for the metal-free coupling of 4-, 5-, and 6-membered satd. heterocyclic p-methoxyphenyl (PMP) sulfonylhydrazones with aryl and heteroarom. boronic acids. This procedure enables a simple, two-step synthesis of a range of functionalized sp2-sp3 linked bicyclic building blocks, including oxetanes, piperidines, and azetidines, from their parent ketones.
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Nassoy, A.-C. M. A.; Raubo, P.; Harrity, J. P. A. Synthesis and Indole Coupling Reactions of Azetidine and Oxetane Sulfinate Salts Chem. Commun. 2015, 51, 5914– 5916 DOI: 10.1039/C5CC00975H
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375
Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Brown, H. S.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Leach, A. G.; MacFaul, P. A.; McKerrecher, D. Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists MedChemComm 2013, 4, 95– 100 DOI: 10.1039/C2MD20130E
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376
Pei, Z.; Blackwood, E.; Liu, L.; Malek, S.; Belvin, M.; Koehler, M. F. T.; Ortwine, D. F.; Chen, H.; Cohen, F.; Kenny, J. R. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349 ACS Med. Chem. Lett. 2013, 4, 103– 107 DOI: 10.1021/ml3003132
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376
Discovery and biological profiling of potent and selective mTOR inhibitor GDC-0349
Pei, Zhonghua; Blackwood, Elizabeth; Liu, Lichuan; Malek, Shiva; Belvin, Marcia; Koehler, Michael F. T.; Ortwine, Daniel F.; Chen, Huifen; Cohen, Frederick; Kenny, Jane R.; Bergeron, Philippe; Lau, Kevin; Ly, Cuong; Zhao, Xianrui; Estrada, Anthony A.; Truong, Tom; Epler, Jennifer A.; Nonomiya, Jim; Trinh, Lan; Sideris, Steve; Lesnick, John; Bao, Linda; Vijapurkar, Ulka; Mukadam, Sophie; Tay, Suzanne; Deshmukh, Gauri; Chen, Yung-Hsiang; Ding, Xiao; Friedman, Lori S.; Lyssikatos, Joseph P.
ACS Medicinal Chemistry Letters (2013), 4 (1), 103-107CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been obsd. in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead I(R = H, Me) culminated in the discovery of clin. development candidate II, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.
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Jadhav, P. K.; Schiffler, M. A.; Gavardinas, K.; Kim, E. J.; Matthews, D. P.; Staszak, M. A.; Coffey, D. S.; Shaw, B. W.; Cassidy, K. C.; Brier, R. A. Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm ACS Med. Chem. Lett. 2014, 5, 1138– 1142 DOI: 10.1021/ml500283g
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Schoenfeld, R. C.; Bourdet, D. L.; Brameld, K. A.; Chin, E.; de Vicente, J.; Fung, A.; Harris, S. F.; Lee, E. K.; Le Pogam, S.; Leveque, V. Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B J. Med. Chem. 2013, 56, 8163– 8182 DOI: 10.1021/jm401266k
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378
Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B
Schoenfeld, Ryan C.; Bourdet, David L.; Brameld, Ken A.; Chin, Elbert; de Vicente, Javier; Fung, Amy; Harris, Seth F.; Lee, Eun K.; Le Pogam, Sophie; Leveque, Vincent; Li, Jim; Lui, Alfred S.-T.; Najera, Isabel; Rajyaguru, Sonal; Sangi, Michael; Steiner, Sandra; Talamas, Francisco X.; Taygerly, Joshua P.; Zhao, Junping
Journal of Medicinal Chemistry (2013), 56 (20), 8163-8182CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Hepatitis C virus (HCV) is a major global public health problem. While the current std. of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed to provide a clin. candidate in fluoropyridone (I).
379
Gonzalez, A. Z.; Eksterowicz, J.; Bartberger, M. D.; Beck, H. P.; Canon, J.; Chen, A.; Chow, D.; Duquette, J.; Fox, B. M.; Fu, J. Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction J. Med. Chem. 2014, 57, 2472– 2488 DOI: 10.1021/jm401767k
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379
Selective and Potent Morpholinone Inhibitors of the MDM2-p53 Protein-Protein Interaction
Gonzalez, Ana Z.; Eksterowicz, John; Bartberger, Michael D.; Beck, Hilary P.; Canon, Jude; Chen, Ada; Chow, David; Duquette, Jason; Fox, Brian M.; Fu, Jiasheng; Huang, Xin; Houze, Jonathan B.; Jin, Lixia; Li, Yihong; Li, Zhihong; Ling, Yun; Lo, Mei-Chu; Long, Alexander M.; McGee, Lawrence R.; McIntosh, Joel; McMinn, Dustin L.; Oliner, Jonathan D.; Osgood, Tao; Rew, Yosup; Saiki, Anne Y.; Shaffer, Paul; Wortman, Sarah; Yakowec, Peter; Yan, Xuelei; Ye, Qiuping; Yu, Dongyin; Zhao, Xiaoning; Zhou, Jing; Olson, Steven H.; Medina, Julio C.; Sun, Daqing
Journal of Medicinal Chemistry (2014), 57 (6), 2472-2488CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogs led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 (I) emerged as an inhibitor with remarkable biochem. potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. I also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
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Austin, W. F.; Hubbs, J. L.; Fuller, N. O.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M. B.; Findeis, M. A.; Tate, B.; Ives, J. L.; Bronk, B. S. SAR Investigations on a Novel Class of Gamma-Secretase Modulators Based on a Unique Scaffold MedChemComm 2013, 4, 569– 574 DOI: 10.1039/c3md20357c
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Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M. B.; Tate, B.; Xia, W.; Ives, J. Optimization of a Natural Product-Based Class of γ-Secretase Modulators J. Med. Chem. 2012, 55, 9270– 9282 DOI: 10.1021/jm300976b
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381
Optimization of a Natural Product-Based Class of γ-Secretase Modulators
Hubbs, Jed L.; Fuller, Nathan O.; Austin, Wesley F.; Shen, Ruichao; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey; Bronk, Brian S.
Journal of Medicinal Chemistry (2012), 55 (21), 9270-9282CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compds. with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochem. properties of the analogs. This strategy gave compds. with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compds., I and II, were tested for a pharmacodynamic effect and exhibited statistically significant lowering of brain Aβ42 levels.
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Procopiou, P. A.; Barrett, J. W.; Barton, N. P.; Begg, M.; Clapham, D.; Copley, R. C. B.; Ford, A. J.; Graves, R. H.; Hall, D. A.; Hancock, A. P. Synthesis and Structure–Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists J. Med. Chem. 2013, 56, 1946– 1960 DOI: 10.1021/jm301572h
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Synthesis and Structure-Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists
Procopiou, Panayiotis A.; Barrett, John W.; Barton, Nicholas P.; Begg, Malcolm; Clapham, David; Copley, Royston C. B.; Ford, Alison J.; Graves, Rebecca H.; Hall, David A.; Hancock, Ashley P.; Hill, Alan P.; Hobbs, Heather; Hodgson, Simon T.; Jumeaux, Coline; Lacroix, Yannick M. L.; Miah, Afjal H.; Morriss, Karen M. L.; Needham, Deborah; Sheriff, Emma B.; Slack, Robert J.; Smith, Claire E.; Sollis, Steven L.; Staton, Hugo
Journal of Medicinal Chemistry (2013), 56 (5), 1946-1960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A series of indazole arylsulfonamides were synthesized and examd. as human CCR4 antagonists. Methoxy- or hydroxyl- contg. groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogs being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]- group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogs, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compd. with high absorption in two species was analog I (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramol. interaction in the active conformation.
383
Dineen, T. A.; Chen, K.; Cheng, A. C.; Derakhchan, K.; Epstein, O.; Esmay, J.; Hickman, D.; Kreiman, C. E.; Marx, I. E.; Wahl, R. C. Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718) J. Med. Chem. 2014, 57, 9811– 9831 DOI: 10.1021/jm5012676
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383
Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718)
Dineen, Thomas A.; Chen, Kui; Cheng, Alan C.; Derakhchan, Katayoun; Epstein, Oleg; Esmay, Joel; Hickman, Dean; Kreiman, Chuck E.; Marx, Isaac E.; Wahl, Robert C.; Wen, Paul H.; Weiss, Matthew M.; Whittington, Douglas A.; Wood, Stephen; Fremeau, Robert T.; White, Ryan D.; Patel, Vinod F.
Journal of Medicinal Chemistry (2014), 57 (23), 9811-9831CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compds. exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compd. with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compd. produced robust and sustained redns. of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
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Pierson, P. D.; Fettes, A.; Freichel, C.; Gatti-McArthur, S.; Hertel, C.; Huwyler, J.; Mohr, P.; Nakagawa, T.; Nettekoven, M.; Plancher, J.-M. 5-Hydroxyindole-2-carboxylic Acid Amides: Novel Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity J. Med. Chem. 2009, 52, 3855– 3868 DOI: 10.1021/jm900409x
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385
Adrian Meredith, J.; Wallberg, H.; Vrang, L.; Oscarson, S.; Parkes, K.; Hallberg, A.; Samuelsson, B. Design and Synthesis of Novel P2 Substituents in Diol-Based HIV Protease Inhibitors Eur. J. Med. Chem. 2010, 45, 160– 170 DOI: 10.1016/j.ejmech.2009.09.038
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386
Oscarsson, K.; Classon, B.; Kvarnström, I.; Hallberg, A.; Samuelsson, B. Solid Phase Assisted Synthesis of HIV-1 Protease Inhibitors. Expedient Entry to Unsymmetrical Substitution of a C2 Symmetric Template Can. J. Chem. 2000, 78, 829– 837 DOI: 10.1139/v00-012
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387
Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, K.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D. The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α J. Med. Chem. 2012, 55, 8007– 8020 DOI: 10.1021/jm300867c
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387
The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α
Heffron, Timothy P.; Salphati, Laurent; Alicke, Bruno; Cheong, Jonathan; Dotson, Jennafer; Edgar, Kyle; Goldsmith, Richard; Gould, Stephen E.; Lee, Leslie B.; Lesnick, John D.; Lewis, Cristina; Ndubaku, Chudi; Nonomiya, Jim; Olivero, Alan G.; Pang, Jodie; Plise, Emile G.; Sideris, Steve; Trapp, Sean; Wallin, Jeffrey; Wang, Lan; Zhang, Xiaolin
Journal of Medicinal Chemistry (2012), 55 (18), 8007-8020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, the authors report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. The authors leveraged the authors' historical experience with PI3K inhibitors to identify correlations between physicochem. properties and transporter efflux as well as metabolic stability to focus the selection of mols. for further study.
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Patel, S.; Cohen, F.; Dean, B. J.; De La Torre, K.; Deshmukh, G.; Estrada, A. A.; Ghosh, A. S.; Gibbons, P.; Gustafson, A.; Huestis, M. P. Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models J. Med. Chem. 2015, 58, 401– 418 DOI: 10.1021/jm5013984
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Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models
Patel, Snahel; Cohen, Frederick; Dean, Brian J.; De La Torre, Kelly; Deshmukh, Gauri; Estrada, Anthony A.; Ghosh, Arundhati Sengupta; Gibbons, Paul; Gustafson, Amy; Huestis, Malcolm P.; Le Pichon, Claire E.; Lin, Han; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Ly, Cuong Q.; Lyssikatos, Joseph P.; Ma, Changyou; Scearce-Levie, Kimberly; Shin, Young G.; Solanoy, Hilda; Stark, Kimberly L.; Wang, Jian; Wang, Bei; Zhao, Xianrui; Lewcock, Joseph W.; Siu, Michael
Journal of Medicinal Chemistry (2015), 58 (1), 401-418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here the authors describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike mols., the authors came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. The lead inhibitor GNE-3511 I displayed concn.-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacol. inhibition of DLK may have therapeutic potential in multiple indications.
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Chen, L.; Feng, L.; Feng, S.; Gao, L.; Guo, T.; Huang, M.; Liang, C.; Liu, Y.; Wang, L.; Wong, J. C. (F. Hoffmann-La Roche AG). Preparation of Benzothiazepines and Analogs for the Treatment and Prophylaxis of Respiratory Syncytial Virus Infection. International Patent WO 2013020993 A1, 2013.
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Chen, J.; Ren, Y.; She, J.; Wang, L.; Yu, J.; Zhang, G. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Process for the Preparation of N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methylquinazolin-4-amine. International Patent WO 2015110446 A1, 2015.
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Bhatnagar, P. K.; Hartmann, M.; Hiebl, J.; Kremminger, P.; Rovenszky, F. (SmithKline Beecham Corp.; Nycomed Austria GmbH). Pharmaceutical Compositions Containing Substituted Alkylenebisamides for Hemoregulation. International Patent WO 9717964 A1, 1997.
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Brodney, M. A. (Pfizer Products Inc.). Preparation of Pyridyl-Lactams as 5-HT1 Receptors Ligands. International Patent WO 2006106416 A1, 2006.
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Berthel, S. J.; Kester, R. F.; Murphy, D. E.; Prins, T. J.; Ruebsam, F.; Sarabu, R.; Tran, C. V.; Vourloumis, D. (Hoffmann-La Roche Inc.). Preparation of Pyrazole Derivatives as Glucokinase Activators. U.S. Patent US 20080021032 A1, 2008.
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Felding, J.; Nielsen, S. F.; Larsen, J. C. H.; Babu, B. R. (Leo Pharma A/S). Preparation of Spirobenzodioxoles and Spirobenzodioxepins as Phosphodiesterase PDE4 Inhibitors. International Patent WO 2008104175 A2, 2008; .
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Ahrendt, K. A.; Buckmelter, A. J.; De Meese, J.; Grina, J.; Hansen, J. D.; Laird, E. R.; Lunghofer, P.; Moreno, D.; Newhouse, B.; Ren, L. (Array BioPharma Inc.; Genentech, Inc.). N-Pyrazolo[3,4-b]pyridinyl Benzamide Derivatives as Raf Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Diseases. International Patent WO 2009111279 A1, 2009.
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Labadie, S. S.; Lin, C. J. J.; Talamas, F. X.; Weikert, R. J. (F. Hoffmann-La Roche AG). Benzofuran-3-carboxamide Derivatives and Their Pharmaceutical Compositions as Antiviral Agents Useful in the Treatment of Hepatitis C Infection and Preparation Thereof. International Patent WO 2009101022 A1, 2009.
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Chen, L.; Firooznia, F.; Gillespie, P.; He, Y.; Lin, T.-A.; Mertz, E.; So, S.-S.; Yun, H.; Zhang, Z. (F. Hoffmann-La Roche AG). Preparation of Naphthylacetic Acids as Antagonists or Partial Agonists at the CRTH2 Receptor. International Patent WO 2010055004 A1, 2010.
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Fessard, T.; Li, D.-B.; Barbaras, D.; Wolfrum, S.; Carreira, E. (Lipideon Biotechnology AG). Preparation of Azetidinone-Containing Compounds for Pharmaceutical Hypocholesterolemic Compositions. International Patent WO 2010100255 A1, 2010.
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Bleicher, K.; Flohr, A.; Groebke Zbinden, K.; Gruber, F.; Koerner, M.; Kuhn, B.; Peters, J.-U.; Rodriguez Sarmiento, R. M. (F. Hoffmann-La Roche AG). Nitrogen-Containing Heteroaryl Compounds as PDE10A Inhibitors and Their Preparation and Use in the Treatment of Diseases. International Patent WO 2011154327 A1, 2011.
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Boys, M. L.; Burgess, L. E.; Groneberg, R. D.; Harvey, D. M.; Huang, L.; Kercher, T.; Kraser, C. F.; Laird, E.; Tarlton, E.; Zhao, Q. (Array BioPharma Inc.). Imidazo[1,2-c]pyrimidine Derivatives as JAK Inhibitors and Their Preparation and Use for the Treatment of Autoimmune and Inflammatory Diseases. International Patent WO 2011130146 A1, 2011.
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Nielsen, S. F.; Horneman, A. M.; Lau, J. F.; Larsen, J. C. H. (Leo Pharma A/S). Biaryl Derivatives as Phosphodiesterase Inhibitors and Their Preparation and Use in the Treatment of Diseases. International Patent WO 2011134468 A1, 2011.
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Saxty, G.; Murray, C. W.; Berdini, V.; Besong, G. E.; Hamlett, C. C. F.; Johnson, C. N.; Woodhead, S. J.; Reader, M.; Rees, D. C.; Mevellec, L. A., (Astex Therapeutics Ltd.). Preparation of Pyrazolylquinazoline Derivatives for Use as Kinase Inhibitors. International Patent WO 2011135376 A1, 2011.
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Young, J.; Czako, B.; Altman, M.; Guerin, D.; Martinez, M.; Rivkin, A.; Wilson, K.; Lipford, K.; White, C.; Surdi, L., (Merck Sharp & Dohme Corp.). Pyridazinones as Tyrosine Kinase Inhibitors and Their Preparation and Use in the Treatment of Cancer. International Patent WO 2011084402 A1, 2011; .
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Asymmetric Synthesis of 2 Substituted Oxetan-3-ones via Metalated SAMP/RAMP Hydrazones
Geden, Joanna V.; Beasley, Benjamin O.; Clarkson, Guy J.; Shipman, Michael
Journal of Organic Chemistry (2013), 78 (23), 12243-12250CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
2-Substituted oxetan-3-ones can be prepd. in good yields and enantioselectivities (up to 84% ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Addnl., both chiral 2,2- and 2,4-disubstituted oxetan-3-ones can be made in high ee (86-90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aq. oxalic acid provides the 2-substituted oxetan-3-ones without detectable racemization.
444
Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. The SAMP-/RAMP-Hydrazone Methodology in Asymmetric Synthesis Tetrahedron 2002, 58, 2253– 2329 DOI: 10.1016/S0040-4020(02)00080-7
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Job, Andreas; Janeck, Carsten F.; Bettray, Wolfgang; Peters, Rene; Enders, Dieter
Tetrahedron (2002), 58 (12), 2253-2329CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
A review. Stereoselective reactions of SAMP hydrazones, i,.e., N-alkylidene-(2S)-2-(methoxymethyl)-1-pyrrolidinamine derivs., and of RAMP hydrazones, i.e., N-alkylidene-(2R)-2-(methoxymethyl)-1-pyrrolidinamine derivs., were discussed.
445
Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Exploiting the Lithiation-Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2-Aryloxetane Scaffolds under Mild Conditions Angew. Chem., Int. Ed. 2012, 51, 7532– 7536 DOI: 10.1002/anie.201109113
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Ravelli, Davide; Zoccolillo, Matteo; Mella, Mariella; Fagnoni, Maurizio
Advanced Synthesis & Catalysis (2014), 356 (13), 2781-2786CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
The selective C(sp3)-H activation at position 2 in oxetanes was accomplished by decatungstate photocatalysis under mild conditions. The resulting α-oxy radicals were trapped by electron-poor olefins resulting in the smooth prepn. of 2-substituted oxetanes. The chemoselectivity in hydrogen abstraction in substituted oxetanes contg. other H donating groups, such as CH2OH, CH2OAc and CHO, was demonstrated in intramol. models.
448
Jin, J.; MacMillan, D. W. C. Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C-H Functionalization and the Minisci Reaction Angew. Chem., Int. Ed. 2015, 54, 1565– 1569 DOI: 10.1002/anie.201410432
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Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C-H Functionalization and the Minisci Reaction
Jin, Jian; MacMillan, David W. C.
Angewandte Chemie, International Edition (2015), 54 (5), 1565-1569CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The direct α-arylation of cyclic and acyclic ethers with heteroarenes was accomplished through the design of a photoredox-mediated C-H functionalization pathway. Transiently generated α-oxyalkyl radicals, produced from a variety of widely available ethers through hydrogen atom transfer, were coupled with a range of electron-deficient heteroarenes in a Minisci-type mechanism. This mild, visible-light-driven protocol allowed direct access to medicinal pharmacophores of broad utility using feedstock substrates and a com. photocatalyst.
449
Ahlgren, G. Reactions of Lone Pair Electron Donors with Unsaturated Electrophiles. I. The Addition of Tetrahydrofuran and Oxetane to Dimethyl Acetylenedicarboxylate J. Org. Chem. 1973, 38, 1369– 1374 DOI: 10.1021/jo00947a028
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Journal of Organic Chemistry (1996), 61 (21), 7248-7249CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The prepn. of 2-methyleneoxetanes by a novel application of Petasis methylenation to β-lactones is delineated. The methylenation of the β-lactone occurs preferentially in the presence of alkenes and ketones.
457
Dollinger, L. M.; Howell, A. R. A 2-Methyleneoxetane Analogue of Orlistat Demonstrating Inhibition of Porcine Pancreatic Lipase Bioorg. Med. Chem. Lett. 1998, 8, 977– 978 DOI: 10.1016/S0960-894X(98)00140-1
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Zhi, J.; Melia, A. T.; Guerciolini, R.; Chung, J.; Kinberg, J.; Hauptman, J. B.; Patel, I. H. Retrospective Population-Based Analysis of the Dose-Response (Fecal Fat Excretion) Relationship of Orlistat in Normal and Obese Volunteers Clin. Pharmacol. Ther. 1994, 56, 82– 85 DOI: 10.1038/clpt.1994.104
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Clinical pharmacology and therapeutics (1994), 56 (1), 82-5 ISSN:0009-9236.
Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.
459
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Fang, Yewen; Li, Chaozhong
Journal of the American Chemical Society (2007), 129 (26), 8092-8093CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The copper-catalyzed intramol. O-vinylation of γ-bromohomoallylic alcs. was investigated. With 10 mol % of CuI as the catalyst and 20 mol % of 1,10-phenanthroline as the ligand, the reactions of 3-bromo-3-buten-1-ols, e.g. I, in refluxing CH3CN led to the convenient formation of the corresponding 2-methyleneoxetanes, e.g. II, in good to excellent yields via a 4-exo ring closure. The configuration of the C:C bond was nicely retained. This methodol. was then successfully extended to the cyclization in 5-exo, 6-exo, and even 6-endo modes. The competition expts. revealed that 4-exo cyclization is fundamentally preferred over other modes of cyclization, while the corresponding Pd(0)-catalyzed O-vinylation showed the predominance of 5-exo over 4-exo cyclization.
462
Saunders, L. B.; Miller, S. J. Divergent Reactivity in Amine- and Phosphine-Catalyzed C–C Bond-Forming Reactions of Allenoates with 2,2,2-Trifluoroacetophenones ACS Catal. 2011, 1, 1347– 1350 DOI: 10.1021/cs200406d
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Divergent Reactivity in Amine- and Phosphine-Catalyzed C-C Bond-Forming Reactions of Allenoates with 2,2,2-Trifluoroacetophenones
Saunders, Lindsey B.; Miller, Scott J.
ACS Catalysis (2011), 1 (10), 1347-1350CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
A divergent reactivity pattern of allenoates with 2,2,2-trifluoroacetophenones under Lewis base catalysis is reported. Whereas phosphine catalysis leads to a [3 + 2]-cycloaddn. to form dihydrofurans, an alternative pathway was discovered in which 1,4-diazabicyclo[2.2.2]octane catalyzes a formal [2 + 2]-cycloaddn. to form oxetanes. This unusual mode of reactivity leads to structurally complex products in moderate to excellent yields (32-86%) and adds to the repertoire of Lewis base-catalyzed allenoate transformations.
463
Wang, T.; Chen, X.-Y.; Ye, S. DABCO-Catalyzed [2+2] Cycloaddition Reactions of Allenoates and Trifluoromethylketones: Synthesis of 2-Alkyleneoxetanes Tetrahedron Lett. 2011, 52, 5488– 5490 DOI: 10.1016/j.tetlet.2011.08.057
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Zhao, Q.-Y.; Huang, L.; Wei, Y.; Shi, M. Catalytic Asymmetric Synthesis of 2-Alkyleneoxetanes Through [2+2] Annulation of Allenoates with Trifluoromethyl Ketones Adv. Synth. Catal. 2012, 354, 1926– 1932 DOI: 10.1002/adsc.201200237
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Catalytic Asymmetric Synthesis of 2-Alkyleneoxetanes through [2+2] Annulation of Allenoates with Trifluoromethyl Ketones
Zhao, Qian-Yi; Huang, Long; Wei, Yin; Shi, Min
Advanced Synthesis & Catalysis (2012), 354 (10), 1926-1932, S1926/1-S1926/72CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first example of a β-isocupreidine-catalyzed highly enantioselective [2+2] annulation of allenoates with trifluoromethyl ketones has been disclosed, allowing the synthesis of optically active 2-alkyleneoxetanes in moderate to good yields with good to high enantioselectivities and high diastereoselectivities. E.g., in presence of β-isocupreidine, enantioselective [2+2] annulation of benzyl 2,3-butadienoate and PhCOCF3 gave 74% oxetane (S)-(E)-I. Further transformations of the cycloadducts have been disclosed to afford biol. interesting 6-trifluoromethyl-5,6-dihydropyran-2-ones and trifluoromethyl β-keto acids in good yields.
465
Selig, P.; Turočkin, A.; Raven, W. Synthesis of Highly Substituted Oxetanes via [2+2] Cycloaddition Reactions of Allenoates Catalyzed by a Guanidine Lewis Base Chem. Commun. 2013, 49, 2930– 2932 DOI: 10.1039/c3cc40855h
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465
Synthesis of highly substituted oxetanes via [2+2] cycloaddition reactions of allenoates catalyzed by a guanidine Lewis base
Selig, Philipp; Turockin, Aleksej; Raven, William
Chemical Communications (Cambridge, United Kingdom) (2013), 49 (28), 2930-2932CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
The first synthesis of highly substituted 3-alkyl-oxetan-2-ylidenes from allenoates was developed by using the bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as an exceptionally active nitrogen Lewis base catalyst.
466
Selig, P.; Turočkin, A.; Raven, W. Guanidine-Catalyzed Triple Functionalization of γ-Substituted Allenoates with Aldehydes by a Four-Step Reaction Cascade Adv. Synth. Catal. 2013, 355, 297– 302 DOI: 10.1002/adsc.201200807
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466
Guanidine-catalyzed triple functionalization of γ-substituted allenoates with aldehydes by a four-step reaction cascade
Selig, Philipp; Turockin, Aleksej; Raven, William
Advanced Synthesis & Catalysis (2013), 355 (2-3), 297-302CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
The bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was discovered as an efficient catalyst for the reaction of γ-substituted allenoates with arom. aldehydes. 4H-1,3-Dioxin-6-ylpropanoates with four newly formed bonds and four stereogenic centers were obtained in good yields and excellent diastereoselectivities by two consecutive Morita-Baylis-Hillman reactions, acetalization and intramol. Michael addn. This four-step reaction cascade not only significantly expands the scope of catalytic allenoate functionalizations but also highlights the potential of TBD to act as a multifunctional Lewis base catalyst.
467
Dollinger, L. M.; Howell, A. R. An Unanticipated Ring Opening of 2-Methyleneoxetanes: A Fundamentally New Approach to the Preparation of Homopropargylic Alcohols J. Org. Chem. 1998, 63, 6782– 6783 DOI: 10.1021/jo9816360
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468
Wang, Y.; Bekolo, H.; Howell, A. R. Ring Opening Reactions of 2-Methyleneoxetanes Tetrahedron 2002, 58, 7101– 7107 DOI: 10.1016/S0040-4020(02)00724-X
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468
Ring opening reactions of 2-methyleneoxetanes
Wang, Ying; Bekolo, Henri; Howell, Amy R.
Tetrahedron (2002), 58 (35), 7101-7107CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
Ring opening of 2-methyleneoxetanes with stabilized carbanion nucleophiles provides substituted ketones. The intermediate enolate can be trapped as its silylenol ether. If the 2-methyleneoxetane is exposed to more strongly basic carbanions, the corresponding homopropargylic alc. is isolated in excellent yield. A variety of heteroatom nucleophiles also open the 2-methyleneoxetane in good to excellent yields.
469
Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang, G.; Wang, Y.; Martinez, I.; Arcari, J. T.; Galluzzo, D. J.; Howell, A. R.; Rheingold, A. L.; Figuero, J. S. Preparation and Properties of 2-Methyleneoxetanes J. Org. Chem. 1999, 64, 7074– 7080 DOI: 10.1021/jo9906072
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469
Preparation and properties of 2-methyleneoxetanes
Dollinger, Lisa M.; Ndakala, Albert J.; Hashemzadeh, Mehrnoosh; Wang, Gan; Wang, Ying; Martinez, Isamir; Arcari, Joel T.; Galluzzo, David J.; Howell, Amy R.; Rheingold, Arnold L.; Figuero, Joshua S.
Journal of Organic Chemistry (1999), 64 (19), 7074-7080CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The methylenation of β-lactones I [R, R1 = H, Me, Ph, allyl, 5-hexenoyl, Bz, PhC(O-TBDMS)H, TBDPS-OCH2CH2, 3-butenyl, Boc-NH, etc. (TBDMS = Me3CSiMe2; TBDPS = Me3CSiPh2; Boc = Me3CO2C)] with dimethyltitanocene provides a versatile, reliable, and highly chemoselective entry to 2-methyleneoxetanes II. The conversion proceeds selectively in the presence of alkenes, unprotected alcs., and a variety of other carbonyl moieties. A study of conditions for the optimization of this reaction is delineated. In addn., the first x-ray crystal structure of a 2-methyleneoxetane S-II (R = BocNH, R1 = R2 = H), which shows its similarity to related β-lactones, is reported. Reactivity studies of 2-methyleneoxetanes are presented in which it is demonstrated that these compds. are attacked at C-4 with a nucleophile and then, subsequently, the resultant enolate reacted with an electrophile. An interesting dichotomy of reactivity was obsd. when methyleneoxetane II (R = Ph; R1 = Me; R2 = H) (III) was treated with electrophiles. Reaction of III with acetic acid gave acetoxyoxetane IV. When III was exposed to bromine, dibromo ketone BrCH2C(Ph)MeCOCH2Br resulted.
470
Hashemzadeh, M.; Howell, A. R. Reductive Cleavage of 2-Methyleneoxetanes with Lithium and 4, 4′-Di-tert-butylbiphenyl Tetrahedron Lett. 2000, 41, 1855– 1858 DOI: 10.1016/S0040-4039(00)00059-9
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471
Hashemzadeh, M.; Howell, A. R. An Unusual and Efficient Reaction of 2-Methylene-3-Phenyloxetane in the Presence of Lithium and 4,4′-Di-Tert-Butylbiphenyl in THF Tetrahedron Lett. 2000, 41, 1859– 1862 DOI: 10.1016/S0040-4039(00)00060-5
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472
Farber, E.; Rudnitskaya, A.; Keshipeddy, S.; Lao, K. S.; Gascón, J. A.; Howell, A. R. Silicon Acceleration of a Tandem Alkene Isomerization/Electrocyclic Ring-opening of 2-Methyleneoxetanes to α,β-Unsaturated Methylketones J. Org. Chem. 2013, 78, 11213– 11220 DOI: 10.1021/jo4014645
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472
Silicon Acceleration of a Tandem Alkene Isomerization/Electrocyclic Ring-opening of 2-Methyleneoxetanes to α,β-Unsaturated Methylketones
Farber, Elisa; Rudnitskaya, Aleksandra; Keshipeddy, Santosh; Lao, Kendricks S.; Gascon, Jose A.; Howell, Amy R.
Journal of Organic Chemistry (2013), 78 (22), 11213-11220CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The first rearrangement of 2-methyleneoxetanes to α,β-unsatd. methylketones is reported. It is proposed that when these substrates are heated, the corresponding oxetenes are formed and subsequently undergo electrocyclic ring-opening to Me vinyl ketones. In particular, α-silyl-α,β-unsatd. Me ketones were isolated in moderate to high yields and with high stereoselectivities. Based on the proposed mechanism, d. functional theory explains the differential kinetics and stereoselectivities among substrates.
473
Ferrer, M.; Gibert, M.; Sánchez-Baeza, F.; Messeguer, A. Easy Availability of More Concentrated and Versatile Dimethyldioxirane Solutions Tetrahedron Lett. 1996, 37, 3585– 3586 DOI: 10.1016/0040-4039(96)00628-4
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473
Easy availability of more concentrated and versatile dimethyldioxirane solutions
Ferrer, Marta; Gilbert, Mariona; Sanchez-Baeza, Francisco; Messeguer, Angel
Tetrahedron Letters (1996), 37 (20), 3585-3586CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
Useful and more concd. solns. of dimethyldioxirane were obtained by extn. with CH2Cl2, CHCl3, or CCl4 and subsequent washing with a phosphate buffer soln.
474
Howell, A. R.; Ndakala, A. J. Ring Opening of Ketones or 2,2-Disubstituted Oxetanes Org. Lett. 1999, 1, 825– 827 DOI: 10.1021/ol990039c
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475
Taboada, R.; Ordonio, G. G.; Ndakala, A. J.; Howell, A. R.; Rablen, P. R. Directed Ring-Opening of 1,5-Dioxaspiro[3.2]hexanes: Selective Formation of 2,2-Disubstituted Oxetanes J. Org. Chem. 2003, 68, 1480– 1488 DOI: 10.1021/jo0206465
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475
Directed Ring-Opening of 1,5-Dioxaspiro[3.2]hexanes: Selective Formation of 2,2-Disubstituted Oxetanes
Taboada, Rosa; Ordonio, Grace G.; Ndakala, Albert J.; Howell, Amy R.; Rablen, Paul R.
Journal of Organic Chemistry (2003), 68 (4), 1480-1488CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
1,5-Dioxaspiro[3.2]hexanes undergo ring-opening reactions with many heteroatom nucleophiles to provide α-substituted-β'-hydroxy ketones. However, certain Lewis acidic nucleophiles provide 2,2-disubstituted oxetanes. Herein, the results of reactions of 3-phenyl-1,5-dioxaspiro[3.2]hexane with a variety of N-contg. heteroarom. bases are reported. There appears to be a correlation between the pKa of the nucleophile and the reaction outcome with more acidic nucleophiles providing 2,2-disubstituted oxetanes. also, the mode of ring opening can be directed toward the substituted oxetane by the addn. of a Lewis acid. These results are rationalized by calcn. of stationary points on the potential energy surfaces for the various possible reaction pathways using ab initio MO methods.
476
Ndakala, A. J.; Hashemzadeh, M.; So, R. C.; Howell, A. R. Synthesis of D-erythro-Dihydrosphingosine and D-xylo-Phytosphingosine from a Serine-Derived 1,5-Dioxaspiro[3.2]hexane Template Org. Lett. 2002, 4, 1719– 1722 DOI: 10.1021/ol0200448
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477
Blauvelt, M. L.; Howell, A. R. Synthesis of epi-Oxetin via a Serine-Derived 2-Methyleneoxetane J. Org. Chem. 2008, 73, 517– 521 DOI: 10.1021/jo7018762
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478
Keshipeddy, S.; Martínez, I.; Castillo, B. F.; Morton, M. D.; Howell, A. R. Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles J. Org. Chem. 2012, 77, 7883– 7890 DOI: 10.1021/jo301048z
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478
Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles
Keshipeddy, Santosh; Martinez, Isamir; Castillo, Bernard F.; Morton, Martha D.; Howell, Amy R.
Journal of Organic Chemistry (2012), 77 (18), 7883-7890CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
(compd. nos. in this abstr. correspond to their resp. Roman numerals in the graphic.). Laureatin (1), a metabolite of the red algae Laurencia nipponica, has shown potent activity as a mosquito larvicide. The two previously published syntheses of laureatin involved an initial prepn. of the 8-membered cyclic ether, followed by formation of the oxetane ring. Our strategy was the reverse, i.e., to utilize an oxetane as the framework to construct the larger ring. During this work, attempted N-bromosuccinimide (NBS)-mediated cyclization of oxetane alc. 17, prepd. from readily accessible 2-methyleneoxetane 12, yielded epoxytetrahydrofuran 19 rather than the expected laureatin core. Further derivatization of 19 yielded trans fused bis-tetrahydrofuran 32. The synthesis of 19 and 32, as well as structural and stereochem. elucidation studies, are described.
479
Wang, G.; Wang, Y.; Arcari, J. T.; Howell, A. R.; Rheingold, A. L.; Concolino, T. 1-Iodomethyl-3,4-diphenyl-2,6-dioxabicyclo[2.2.0]hexane: The First Example of a Fused Ketal Tetrahedron Lett. 1999, 40, 7051– 7053 DOI: 10.1016/S0040-4039(99)01469-0
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480
Liang, Y.; Hnatiuk, N.; Rowley, J. M.; Whiting, B. T.; Coates, G. W.; Rablen, P. R.; Morton, M.; Howell, A. R. Access to Oxetane-Containing psico-Nucleosides from 2-Methyleneoxetanes: A Role for Neighboring Group Participation? J. Org. Chem. 2011, 76, 9962– 9974 DOI: 10.1021/jo201565h
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480
Access to Oxetane-Containing psico-Nucleosides from 2-Methyleneoxetanes: A Role for Neighboring Group Participation?
Liang, Yanke; Hnatiuk, Nathan; Rowley, John M.; Whiting, Bryan T.; Coates, Geoffrey W.; Rablen, Paul R.; Morton, Martha; Howell, Amy R.
Journal of Organic Chemistry (2011), 76 (24), 9962-9974CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The first psico-oxetanocin analog of the powerful antiviral natural product, oxetanocin A, has been readily synthesized from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were derived from β-lactones prepd. by the carbonylation of epoxides. F+-mediated nucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. Surprisingly, attempted exploitation of anchimeric assistance to increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepd. to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable.
481
Bekolo, H.; Howell, A. R. Preparation and Reactions of 4-Oxaspiro[2.3]hexanes New J. Chem. 2001, 25, 673– 675 DOI: 10.1039/b010095l
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481
Preparation and reactions of 4-oxaspiro[2.3]hexanes
Bekolo, Henri; Howell, Amy R.
New Journal of Chemistry (2001), 25 (5), 673-675CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
2-Methyleneoxetanes were converted in excellent yields to 4-oxaspiro[2.3]hexanes under modified Simmons-Smith conditions. Treatment of the oxaspirohexanes with BF3·Et2O provided cyclopentanones, cyclobutanones or 4-methylenetetrahydrofurans, depending on the substituents.
482
Furukawa, J.; Kawabata, N.; Nishimura, J. Synthesis of Cyclopropanes by the Reaction of Olefins with Dialkylzinc and Methylene Iodide Tetrahedron 1968, 24, 53– 58 DOI: 10.1016/0040-4020(68)89007-6
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482
Synthesis of cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide
Furukawa, Junji; Kawabata, Nariyoshi; Nishimura, Jun
Tetrahedron (1968), 24 (1), 53-8CODEN: TETRAB; ISSN:0040-4020.
A novel synthetic route to cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide is described. The essential feature of the reaction is similar to that of the Simmons-Smith reaction (CA 60: 13109e) which involves the treatment of olefins with methylene iodide and Zn-Cu couple. However, the novel route gives cyclopropanes more easily and is esp. suitable for the conversion of cationically polymerizable olefins such as vinyl ethers into the corresponding cyclopropanes. Olefins of this class, when the Simmons-Smith reaction is employed, sometimes give lower yields of cyclopropanes due to polymn.
483
Malapit, C. A.; Chitale, S. M.; Thakur, M. S.; Taboada, R.; Howell, A. R. Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans: Scope and Mechanism J. Org. Chem. 2015, 80, 5196– 5209 DOI: 10.1021/acs.joc.5b00604
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483
Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans: Scope and Mechanism
Malapit, Christian A.; Chitale, Sampada M.; Thakur, Meena S.; Taboada, Rosa; Howell, Amy R.
Journal of Organic Chemistry (2015), 80 (10), 5196-5209CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A novel Pt-catalyzed rearrangement of oxaspirohexanes, e.g. I, to 3-methylenetetrahydrofurans, e.g. II, is reported. Mechanistic studies by 13C-labeling expts. confirm oxidative addn. of Pt(II) regioselectively to the least substituted carbon-carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been obsd. spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described.
484
Pritchard, J. G.; Long, F. A. The Kinetics of the Hydrolysis of Trimethylene Oxide in Water, Deuterium Oxide and 40% Aqueous Dioxane 1 J. Am. Chem. Soc. 1958, 80, 4162– 4165 DOI: 10.1021/ja01549a012
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Xianming, H.; Kellogg, R. M. Acid Catalyzed Ring-Opening Reactions of Optically Pure 2-Aryl-3,3-Dimethyloxetanes Tetrahedron: Asymmetry 1995, 6, 1399– 1408 DOI: 10.1016/0957-4166(95)00173-M
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486
Searles, S.; Gregory, V. P. The Reaction of Trimethylene Oxide with Amines J. Am. Chem. Soc. 1954, 76, 2789– 2790 DOI: 10.1021/ja01639a055
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487
Chini, M.; Crotti, P.; Favero, L.; Macchia, F. Mild LiBF₄-Promoted Aminolysis of Oxetanes Tetrahedron Lett. 1994, 35, 761– 764 DOI: 10.1016/S0040-4039(00)75811-4
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Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Aminolysis of Oxetanes: Quite Efficient Catalysis by Lanthanide(III) Trifluoromethansulfonates Tetrahedron Lett. 1994, 35, 7089– 7092 DOI: 10.1016/0040-4039(94)88233-9
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489
Papini, A.; Ricci, A.; Taddei, M.; Seconi, G.; Dembech, P. Regiospecific Conversion of Oxiranes, Oxetanes, and Lactones into Difunctional Nitrogen Compounds via Aminosilanes and Aminostannanes J. Chem. Soc., Perkin Trans. 1 1984, 2261– 2265 DOI: 10.1039/p19840002261
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489
Regiospecific conversion of oxiranes, oxetanes, and lactones into difunctional nitrogen compounds via aminosilanes and aminostannanes
Papini, Annamaria; Ricci, Alfredo; Taddei, Maurizio; Seconi, Giancarlo; Dembech, Pasquale
Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1984), (10), 2261-5CODEN: JCPRB4; ISSN:0300-922X.
Insertion reactions of Me3SiNEt2 (I) and Me3SnNEt2 (II) into oxirane, oxetane, and lactone rings were examd. The Et2AlCl- or AlCl3-catalyzed reactions of monoalkyloxiranes and monoalkyl- or aryloxetanes gave regioisomerically pure β- and γ-amino alcs., resp.; with polysubstituted oxiranes a low of regioselectivity was generally obsd. Ring-opening reactions of the lactone rings with I gave β-amino acids or ω-hydroxy amides, depending on the ring size. With II, spontaneous ring cleavage of alkyloxiranes and of β-propiolactone occurred with reverse regioselectivity, whereas oxetanes and γ- and δ-lactones were opened with the same regioselectivity as that obtained with I for these systems.
490
Fernández-Pérez, H.; Etayo, P.; Núñez-Rico, J. L.; Balakrishna, B.; Vidal-Ferran, A. Ring-Opening of Enantiomerically Pure Oxa-Containing Heterocycles with Phosphorus Nucleophiles RSC Adv. 2014, 4, 58440– 58447 DOI: 10.1039/C4RA10432C
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Ring-opening of enantiomerically pure oxa-containing heterocycles with phosphorus nucleophiles
Fernandez-Perez, Hector; Etayo, Pablo; Nunez-Rico, Jose Luis; Balakrishna, Bugga; Vidal-Ferran, Anton
RSC Advances (2014), 4 (102), 58440-58447CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A series of oxa-contg. heterocycles (enantiopure epoxide- and oxetane-based substrates) were subjected to ring-opening with phosphorus nucleophiles. The ring-opening reactions proceeded smoothly and the resulting 1,2-, and 1,3-phosphino alcs. were efficiently isolated as stable borane complexes. These derivs. arise from regio- and stereocontrolled synthesis based on ring-opening processes of oxa-contg. heterocycles. The regio- and stereochem. of the resulting chiral products were unequivocally confirmed in many cases via single-crystal x-ray diffraction anal.
491
Ng, K.; Tran, V.; Minehan, T. A Single-Flask Synthesis of α-Alkylidene and α-Benzylidene Lactones from Ethoxyacetylene, Epoxides/oxetanes, and Carbonyl Compounds Tetrahedron Lett. 2016, 57, 415– 419 DOI: 10.1016/j.tetlet.2015.12.041
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491
A single-flask synthesis of α-alkylidene and α-benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and carbonyl compounds
Ng, Kevin; Tran, Vincent; Minehan, Thomas
Tetrahedron Letters (2016), 57 (3), 415-419CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
Low temp. treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3·OEt2, followed by addn. of aldehydes or ketones and warming to room temp., affords structurally diverse five- and six-membered α-alkylidene and α-benzylidene lactones in good to excellent yields. This one-pot process, in which three new carbon-carbon bonds and a ring are formed, affords substituted α,β-unsatd. lactones of predominantly Z-configuration. The reaction likely occurs via alkyne-carbonyl metathesis of a hydroxy-ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization.
492
Yamaguchi, M.; Nobayashi, Y.; Hirao, I. The Alkynylation Reaction of Oxetanes Tetrahedron Lett. 1983, 24, 5121– 5122 DOI: 10.1016/S0040-4039(00)94057-7
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Gassman, P. G.; Haberman, L. M. Regiospecfic Opening of Oxetanes with Trimethylsilyl Cyanide – Zinc Iodide. A General Approach to γ-Amino Alcohols Tetrahedron Lett. 1985, 26, 4971– 4974 DOI: 10.1016/S0040-4039(01)80828-5
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Carr, S. A.; Weber, W. P. Titanium Tetrachloride Promoted Reactions of Allylic Trimethylsilanes and Oxetane J. Org. Chem. 1985, 50, 2782– 2785 DOI: 10.1021/jo00215a038
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Searles, S., Jr.; Pollart, K. A.; Lutz, E. F. Oxetanes. VI. 1 Reductive Cleavage and Substituent Effects J. Am. Chem. Soc. 1957, 79, 948– 951 DOI: 10.1021/ja01561a046
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Hudrlik, P. F.; Wan, C.-N. Reactions of Oxetane with Imine Salts Derived from Cyclohexanone J. Org. Chem. 1975, 40, 2963– 2965 DOI: 10.1021/jo00908a027
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Yamaguchi, M.; Shibato, K.; Hirao, I. A New Synthesis of δ-Lactones From Oxetanes Tetrahedron Lett. 1984, 25, 1159– 1162 DOI: 10.1016/S0040-4039(01)91549-7
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A new synthesis of δ-lactones from oxetanes
Yamaguchi, Masahiko; Shibato, Keisuke; Hirao, Ichiro
Tetrahedron Letters (1984), 25 (11), 1159-62CODEN: TELEAY; ISSN:0040-4039.
Oxetanes reacted with lithium enolates generated from esters or amides in the presence of F3B.OEt2 to give δ-hydroxy esters or amides in high yield, which were hydrolyzed and converted to δ-lactones. Thus, AcOCMe3 in THF at -78° was treated with (Me2CH)2NLi in THF-hexane for 25 min and then with heptyloxetane I in THF contg. F3B.OEt2 at -95° to -40° for 1.5 h to give 87% undecanoate II. Treatment of II with F3CCO2H in CH2Cl2 gave undecanolide III quant.
500
Derick, C. G.; Bissell, D. W. Studies of Trimethylene Oxide. I. Preparation and Characterization J. Am. Chem. Soc. 1916, 38, 2478– 2486 DOI: 10.1021/ja02268a023
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Searles, S. The Reaction of Trimethylene Oxide with Grignard Reagents and Organolithium Compounds J. Am. Chem. Soc. 1951, 73, 124– 125 DOI: 10.1021/ja01145a045
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The reaction of trimethylene oxide with Grignard reagents and organolithium compounds
Searles, Scott
Journal of the American Chemical Society (1951), 73 (), 124-5CODEN: JACSAT; ISSN:0002-7863.
Dropwise addn. of 60 g. Cl(CH2)3OAc during 45 min. to 65 g. NaOH, 65 g. KOH, and 5 g. H2O at 150-60° and purification (cf. Noller, C.A. 44, 2443i) gave 42-5% (CH2)3O (I). General procedure: addn. of 0.13-0.20 mole I in 3 vols. anhyd. Et2O to 0.18-0.30 mole RMgX (or RLi occasionally) in cold Et2O (formation of a white ppt.), refluxing 1 hr., addn. of 150-200 cc. C6H6, removal of the Et2O by distn., refluxing 4 hrs., cooling, hydrolysis with satd. NH4Cl, extn. with Et2O or CCl4, and distn. of the org. solns. gave the desired R(CH2)3OH (II), characterized generally as the 3,5-dinitrobenzoate or the 1-naphthylurethan. Data (read R and % yield II): Ph, 84% (also 4% Br(CH2)3OH) (III); Ph, 85% from PhLi; 1-C10H7, 80%; 2-C10H7, 60%; 9-fluorenyl, 44% from RLi; PhCH2, 83%; Bu, 28% from BuLi; cyclohexyl, 28% II, also 40% III; Me2CH, 28% II and 12% III; Me3C, 37% Cl(CH2)3OH. Data for new II (read b.p. and nD20): 1-C10H7, b1 118-19°, 1.615 (phenylurethan, m. 75-6°); 2-C10H7, b7 120-1° (phenylurethan, m. 94°); 9-fluorenyl, b0.2 141° (1-naphthylurethan, m. 124-5°). III was prepd. in 54% yield from 0.2 mole I and 0.5 mole anhyd. MgBr2.
502
Hodgson, D. M.; Norsikian, S. L. M. First Direct Deprotonation–Electrophile Trapping of Simple Epoxides: Synthesis of α,β-Epoxysilanes from Terminal Epoxides Org. Lett. 2001, 3, 461– 463 DOI: 10.1021/ol006948f
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503
Capriati, V.; Florio, S.; Luisi, R. α-Substituted α-Lithiated Oxiranes: Useful Reactive Intermediates Chem. Rev. 2008, 108, 1918– 1942 DOI: 10.1021/cr0683921
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503
α-Substituted α-Lithiated Oxiranes: Useful Reactive Intermediates
Capriati, Vito; Florio, Saverio; Luisi, Renzo
Chemical Reviews (Washington, DC, United States) (2008), 108 (6), 1918-1942CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. This review focuses on generation, reactivity, and synthetic applications of α-metalated oxiranes with special attention addressed to α-lithiated oxiranes.
504
Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Copper-Catalysed Reactions of Grignard Reagents with Epoxides and Oxetane Tetrahedron Lett. 1979, 20, 1503– 1506 DOI: 10.1016/S0040-4039(01)86190-6
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505
Christensen, S. H.; Holm, T.; Madsen, R. Ring-Opening of Cyclic Ethers with Carbon-Carbon Bond Formation by Grignard Reagents Tetrahedron 2014, 70, 4942– 4946 DOI: 10.1016/j.tet.2014.05.026
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506
Bertolini, F.; Crotti, S.; Di Bussolo, V.; Macchia, F.; Pineschi, M. Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates J. Org. Chem. 2008, 73, 8998– 9007 DOI: 10.1021/jo801568a
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506
Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates
Bertolini, Ferruccio; Crotti, Stefano; Di Bussolo, Valeria; Macchia, Franco; Pineschi, Mauro
Journal of Organic Chemistry (2008), 73 (22), 8998-9007CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings I (X = O, NTs; R = Ph, 3-ClC6H4, 4-MeC6H4) with phenols, including catechol, was achieved by the use of aryl borates (ArO)3B (Ar = Ph, 2-FC6H4, 2-I-4-MeO2CC6H3, etc.) under mild and neutral reaction conditions without the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding β-aryloxy amines II (X = NTs) in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to det. the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization obsd. (up to 93:7 er) was rationalized by an intramol. delivery through a six-membered transition state, giving β-aryloxy alcs. II (X = O) with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcs. obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.
507
Dai, P.; Dussault, P. H. Intramolecular Reactions of Hydroperoxides and Oxetanes: Stereoselective Synthesis of 1,2-Dioxolanes and 1,2-Dioxanes Org. Lett. 2005, 7, 4333– 4335 DOI: 10.1021/ol051407h
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507
Intramolecular Reactions of Hydroperoxides and Oxetanes: Stereoselective Synthesis of 1,2-Dioxolanes and 1,2-Dioxanes
Dai, Peng; Dussault, Patrick H.
Organic Letters (2005), 7 (20), 4333-4335CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The 5-exo openings of oxetanes by hydroperoxides proceed rapidly and stereospecifically to furnish 1,2-dioxolanes. The corresponding 6-exo cyclizations are slower and proceed with moderate stereoselectivity. In the case of hydroperoxy acetals, 5-exo nucleophilic transfer of alkoxide competes effectively with 6-exo attack by the hydroperoxide.
508
Han, W. B.; Wu, Y. Facile Perhydrolysis of Oxetanes Catalyzed by Molybdenum Species Org. Lett. 2014, 16, 5706– 5709 DOI: 10.1021/ol502785u
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508
Facile Perhydrolysis of Oxetanes Catalyzed by Molybdenum Species
Han, Wei-Bo; Wu, Yikang
Organic Letters (2014), 16 (21), 5706-5709CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Perhydrolysis of a range of tertiary oxetanes was achieved in synthetically useful yields under mild conditions [e.g., Na2MoO4-gly-catalyzed perhydrolysis of oxetane I with H2O2 in t-BuOMe afforded hydroperoxide II (61%)]. Different functional/protecting groups were tolerated. Similar ring-opening of secondary oxetanes, which had been unfeasible to date, was also realized with ease. With the aid of optically active substrates the perhydrolysis was shown to proceed with significant stereoselectivity.
509
Sugiyama, Y.-K.; Heigozono, S.; Okamoto, S. Iron-Catalyzed Reductive Magnesiation of Oxetanes to Generate (3-Oxidopropyl)magnesium Reagents Org. Lett. 2014, 16, 6278– 6281 DOI: 10.1021/ol503191w
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509
Iron-Catalyzed Reductive Magnesiation of Oxetanes to Generate (3-Oxidopropyl)magnesium Reagents
Sugiyama, Yu-ki; Heigozono, Shiori; Okamoto, Sentaro
Organic Letters (2014), 16 (24), 6278-6281CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
In the presence of FeCln-(bisphosphine) or FeCln-(2-iminomethylpyridine) (n = 2 or 3), 2-substituted oxetanes reacted with Grignard reagents undergoing reductive magnesiation at the 2-position to afford substituted 3-oxidopropylmagnesium compds., which are useful nucleophiles in reactions with a variety of electrophiles.
510
Takekoshi, N.; Miyashita, K.; Shoji, N.; Okamoto, S. Generation of a Low-Valent Titanium Species from Titanatrane and its Catalytic Reactions: Radical Ring Opening of Oxetanes Adv. Synth. Catal. 2013, 355, 2151– 2157 DOI: 10.1002/adsc.201300368
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510
Generation of a Low-Valent Titanium Species from Titanatrane and its Catalytic Reactions: Radical Ring Opening of Oxetanes
Takekoshi, Naoto; Miyashita, Kenji; Shoji, Noriaki; Okamoto, Sentaro
Advanced Synthesis & Catalysis (2013), 355 (11-12), 2151-2157CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
Treatment of a titanatrane complex with trimethylsilyl chloride and magnesium powder in THF generated a low-valent titanium species. This species catalyzed the radical ring opening of epoxides and oxetanes to produce the corresponding less substituted alcs. The reagent also catalyzed the deallylation and depropargylation of allylic and propargylic ethers, resp., to provide the parent alcs.
511
Ishida, N.; Nakanishi, Y.; Murakami, M. Reactivity Change of Cyclobutanols towards Isocyanates: Rhodium Favors C-Carbamoylation over O-Carbamoylation Angew. Chem., Int. Ed. 2013, 52, 11875– 11878 DOI: 10.1002/anie.201306343
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511
Reactivity Change of Cyclobutanols towards Isocyanates: Rhodium Favors C-Carbamoylation over O-Carbamoylation
Ishida, Naoki; Nakanishi, Yuuta; Murakami, Masahiro
Angewandte Chemie, International Edition (2013), 52 (45), 11875-11878CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Rhodium catalysts were found to change the reaction path of cyclobutanol derivs. with isocyanates to form a carbon-carbon bond between the reactants. The process involves a ring opening of a cyclobutane deriv. and proceeds to a direct oxygen-addn. of an isocyanate-oxygen-group. The synthesis of the target compds. was achieved by the action of a cyclobutanol deriv. as carbon nucleophile toward an isocyanate group without loss of a carbonyl group. Bis[(1,2,5,6-η)-1,5-cyclooctadiene]di-μ-(hydroxy)dirhodium (rhodium dimer) and 1,1'-bis(diphenylphosphino)ferrocene were used as catalyst system. The title compds. thus formed included a δ-(oxo)alkanamide deriv. (I) and related substances. Cyclobutanol reactants included (1R,6R,7S)-rel-1-methyl-7-phenylbicyclo[4.2.0]octan-7-ol, 2-phenylspiro[3.5]nonan-2-ol, 3-phenyl-3-oxetanol (cyclobutanol analog).
512
Ng, F. W.; Lin, H.; Danishefsky, S. J. Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine J. Am. Chem. Soc. 2002, 124, 9812– 9824 DOI: 10.1021/ja0204675
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512
Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine
Ng, Fay W.; Lin, Hong; Danishefsky, Samuel J.
Journal of the American Chemical Society (2002), 124 (33), 9812-9824CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The total synthesis of (±)-gelsemine is described. A defining phase of the effort involved recourse to a strategic oxetane ring. It was constructed anticipating an intramol. displacement of the carbon (C17)-oxygen bond. A key intermediate in the stereospecific elaboration of the oxetane linkage was enone I, which was susceptible to two β-face attacks. Three sigmatropic rearrangements were employed in building the bridgehead (C20) and the spiroanilide (C7) quaternary centers en route to gelsemine.
513
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J. The Synthesis of a Key Intermediate En Route to Gelsemine: A Program Based on Intramolecular Displacement of the Carbon-Oxygen Bond of a Strategic Oxetane Tetrahedron Lett. 2002, 43, 545– 548 DOI: 10.1016/S0040-4039(01)02212-2
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514
Bach, T.; Kather, K. Intramolecular Nucleophilic Substitution at the C-4 Position of Functionalized Oxetanes: A Ring Expansion for the Construction of Various Heterocycles J. Org. Chem. 1996, 61, 7642– 7643 DOI: 10.1021/jo961436t
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515
Bach, T.; Kather, K.; Krämer, O. Synthesis of Five-, Six-, and Seven-Membered Heterocycles by Intramolecular Ring Opening Reactions of 3-Oxetanol Derivatives J. Org. Chem. 1998, 63, 1910– 1918 DOI: 10.1021/jo971866z
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516
Boxall, R. J.; Grainger, R. S.; Aricò, C. S.; Ferris, L. Intramolecular Ring-Opening Reactions of 1-(2-Methoxyphenyl)-6-oxabicyclo[3.2.0]heptanes: Spirocyclic Dihydrobenzofurans from Fused Bicyclic Oxetanes Synlett 2008, 2008, 25– 28 DOI: 10.1055/s-2007-990921
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517
Zhao, W.; Wang, Z.; Sun, J. Synthesis of Eight-Membered Lactones: Intermolecular [6 + 2] Cyclization of Amphoteric Molecules with Siloxy Alkynes Angew. Chem., Int. Ed. 2012, 51, 6209– 6213 DOI: 10.1002/anie.201200513
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517
Synthesis of eight-membered lactones: Intermolecular [6+2] cyclization of amphoteric molecules with siloxy alkynes
Zhao, Wanxiang; Wang, Zhaobin; Sun, Jianwei
Angewandte Chemie, International Edition (2012), 51 (25), 6209-6213, S6209/1-S6209/114CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
We have designed a new type of (1,6)-amphoteric mol. by appropriate positioning of the oxetane and aldehyde functional groups within a mol. Enabled by this design, we have successfully demonstrated an efficient [6+2] cyclization process between these (1,6)-amphoteric mols. and siloxy alkynes to form a range of eight-membered lactones. Our method represents the first intermol. reaction for the eight-membered lactone synthesis. Preliminary mechanistic anal. suggests that this unusual process involves a sequence of several selective ring-opening/ring-closing events with concomitant bond formation and cleavage. This approach is now added to the limited no. of strategies available for the elaboration of medium-sized lactones.
518
Yadav, J. S.; Singh, V. K.; Srihari, P. Formation of Substituted Tetrahydropyrans through Oxetane Ring Opening: Application to the Synthesis of C1–C17 Fragment of Salinomycin Org. Lett. 2014, 16, 836– 839 DOI: 10.1021/ol403604u
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518
Formation of Substituted Tetrahydropyrans through Oxetane Ring Opening: Application to the Synthesis of C1-C17 Fragment of Salinomycin
Yadav, J. S.; Singh, Vinay K.; Srihari, P.
Organic Letters (2014), 16 (3), 836-839CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The stereoselective synthesis of C1-C17 fragment I of salinomycin is achieved. The strategy employs a desymmetrization approach and utilizes an intramol. oxetane ring-opening reaction with O-nucleophile to result in the tetrahydropyran skeleton as the key step.
519
Yadav, J. S.; Gyanchander, E.; Das, S. Application of oxetane ring opening toward stereoselective synthesis of zincophorin fragment Tetrahedron Lett. 2014, 55, 3996– 3998 DOI: 10.1016/j.tetlet.2014.05.020
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520
Chang, S.; Hur, S.; Britton, R. Total Synthesis of Ascospiroketal A Through a Ag(I)-Promoted Cyclization Cascade Angew. Chem., Int. Ed. 2015, 54, 211– 214 DOI: 10.1002/anie.201408905
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521
Chang, S.; Hur, S.; Britton, R. Total Synthesis and Configurational Assignment of Ascospiroketal A Chem. - Eur. J. 2015, 21, 16646– 16653 DOI: 10.1002/chem.201502754
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521
Total Synthesis and Configurational Assignment of Ascospiroketal A
Chang, Stanley; Hur, Soo; Britton, Robert
Chemistry - A European Journal (2015), 21 (46), 16646-16653CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The total synthesis of the marine fungus-derived natural product ascospiroketal is described. This concise synthesis relies on a unique AgI-promoted tandem cascade cyclization that provides direct access to the correctly configured tricyclic core of the natural product from a linear precursor. The synthesis of candidate stereostructures of ascospiroketal A allowed for the confident assignment of both the relative and abs. stereochem. of this unusual octaketide as I.
522
Mizuno, M.; Kanai, M.; Iida, A.; Tomioka, K. An External Chiral Ligand Controlled Enantioselective Opening of Oxirane and Oxetane by Organolithiums Tetrahedron 1997, 53, 10699– 10708 DOI: 10.1016/S0040-4020(97)00701-1
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522
An external chiral ligand controlled enantioselective opening of oxirane and oxetane by organolithiums
Mizuno, Masashi; Kanai, Motomu; Iida, Akira; Tomioka, Kiyoshi
Tetrahedron (1997), 53 (31), 10699-10708CODEN: TETRAB; ISSN:0040-4020. (Elsevier)
Enantioselective nucleophilic opening reactions of cyclohexene oxide and 3-phenyloxetane were achieved by the combination of an external chiral ligand and organolithiums in the presence of boron trifluoride to give the corresponding alcs. in up to 47% ee.
523
Loy, R. N.; Jacobsen, E. N. Enantioselective Intramolecular Openings of Oxetanes Catalyzed by (salen)Co(III) Complexes: Access to Enantioenriched Tetrahydrofurans J. Am. Chem. Soc. 2009, 131, 2786– 2787 DOI: 10.1021/ja809176m
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523
Enantioselective Intramolecular Openings of Oxetanes Catalyzed by (salen)Co(III) Complexes: Access to Enantioenriched Tetrahydrofurans
Loy, Rebecca N.; Jacobsen, Eric N.
Journal of the American Chemical Society (2009), 131 (8), 2786-2787CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The catalytic enantioselective intramol. ring-opening of oxetanes with alcs., e.g. I (R = H, Me, Ph, i-Pr, F, etc.), is catalyzed by (salen)Co(III) complexes. Either a monomeric or oligomeric catalyst can be used successfully in this transformation, providing 3-substituted tetrahydrofurans, e.g. II, in both high yield and enantioselectivity. This methodol. extends the range of electrophiles that can be activated toward highly enantioselective addn. reactions by (salen)metal catalysts to an important new class.
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Chen, Z.; Wang, Z.; Sun, J. Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of (+)-(8S,13R)- Cyclocelabenzine Chem. - Eur. J. 2013, 19, 8426– 8430 DOI: 10.1002/chem.201301065
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524
Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of (+)-(8S,13R)-Cyclocelabenzine
Chen, Zhilong; Wang, Zhaobin; Sun, Jianwei
Chemistry - A European Journal (2013), 19 (26), 8426-8430CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The authors have developed a multicomponent method for efficient assembly of tetrahydroisoquinolines, which involves the formation of a C4 stereocenter by means of an enantioselective desymmetrization of oxetanes with amine nucleophiles. These tetrahydroisoquinolines can now be synthesized using a one-step catalytic asym. method that with high efficiency and enantioselectivity. Thus, reacting oxetanylbenzaldehyde I with 3,4,5-trimethoxyaniline in the presence of Hanzstch di-Me ester and phosphoric acid catalyst II gave tetrahydroisoquinoline III in up to 97:3 er. The method was applied to the formal synthesis of alkaloid (+)-(8S,13R)-cyclocelabenzine (IV).
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Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels-Alder Reaction of Indoles with Oxetane as Directing Group Angew. Chem., Int. Ed. 2013, 52, 2027– 2031 DOI: 10.1002/anie.201206481
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525
Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels-Alder Reaction of Indoles with Oxetane as Directing Group
Chen, Zhilong; Wang, Beilei; Wang, Zhaobin; Zhu, Guangyu; Sun, Jianwei
Angewandte Chemie, International Edition (2013), 52 (7), 2027-2031CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first catalytic asym. three-component aza-Diels-Alder reaction using indole as the dienophile was developed. In this reaction, oxetane was shown to be a superb directing group that played a crucial role in achieving both high yields and high enantioselectivities. Thus, in the presence of a chiral phosphoric acid catalyst, I [Ar = C6H2(CHMe2)-2,4,6], a range of complex polycyclic alkaloid-type mols. that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties were rapidly assembled from simple achiral starting materials. The process features efficient formation of multiple bonds (two C-C and two C-N bonds) and multiple (four) chiral centers, rapid installation of mol. complexity, excellent chem. efficiency and stereoselectivity, easy product purifn., and proven biol. activity of the products. This new catalytic asym. multicomponent reaction should be attractive for diversity-oriented synthesis and drug discovery. Further investigations on the reaction mechanism and biol. properties of the polycyclic alkaloid-type products are underway.
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Yang, W.; Sun, J. Organocatalytic Enantioselective Synthesis of 1,4-Dioxanes and Other Oxa-Heterocycles by Oxetane Desymmetrization Angew. Chem., Int. Ed. 2016, 55, 1868– 1871 DOI: 10.1002/anie.201509888
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526
Organocatalytic Enantioselective Synthesis of 1,4-Dioxanes and Other Oxa-Heterocycles by Oxetane Desymmetrization
Yang, Wen; Sun, Jianwei
Angewandte Chemie, International Edition (2016), 55 (5), 1868-1871CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A new asym. synthesis of chiral 1,4-dioxanes and other oxa-heterocycles has been developed by means of organocatalytic enantioselective desymmetrization of oxetanes. This mild process proceeds with exceedingly high efficiency and enantioselectivity to establish the quaternary stereocenters. This method complements the existing, yet limited, strategies for the synthesis of these oxa-heterocycles. Under optimized conditions the synthesis of the target compds. was achieved using (11aR)-10,11,12,13-tetrahydro-5-(hydroxy)-3.7-bis(1-pyrenyl)diindeno[7,1-de:1',7'-fg][1,3,2]dioxaphosphocin as a catalyst. Starting materials included 2-[(3-oxetanyl)oxy]ethanol derivs.
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Yang, W.; Wang, Z.; Sun, J. Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl Angew. Chem., Int. Ed. 2016, 55, 6954– 6958 DOI: 10.1002/anie.201601844
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527
Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl
Yang, Wen; Wang, Zhaobin; Sun, Jianwei
Angewandte Chemie, International Edition (2016), 55 (24), 6954-6958CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
In the presence of a nonracemic spirobiindanephosphoric acid, 3-substituted oxetanes underwent enantioselective ring opening and desymmetrization with chloride generated in situ from trimethoxychlorosilane and water in the presence of 5Å mol. sieves in benzene to yield nonracemic chloropropanols such as (R)-HOCH2CHRCH2Cl [R = Ph, 4-MeC6H4, 2-MeOC6H4, 3-BrC6H4, 3-F3CC6H4, 4-F3CC6H4, 2-naphthyl, 2-benzofuranyl, (E)-PhCH:CH, PhCH2, PhCH2O] as highly functionalized three-carbon building blocks. The excellent enantiocontrol is enabled not only by the use of the new spirobiindanephosphoric acid catalyst, but also by the unusual use of wet mol. sieves for the controlled release of HCl.
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Burkhard, J. A.; Tchitchanov, B. H.; Carreira, E. M. Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes Angew. Chem., Int. Ed. 2011, 50, 5379– 5382 DOI: 10.1002/anie.201100260
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Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes
Burkhard, Johannes A.; Tchitchanov, Boris H.; Carreira, Erick M.
Angewandte Chemie, International Edition (2011), 50 (23), 5379-5382, S5379/1-S5379/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
3-Substituted isoxazole-4-carbaldehydes (I, R = Bn, CH2C6F5, cyclohexylmethyl, CH2CO2Et, etc.) can be prepd. by the condensation reaction of nitroalkanes RCH2NO2 with 3-oxetanone. In general, tertiary amines (in particular iPr2NEt) were superior to other bases in favoring the formation of isoxazoles. The one-pot operation probably involves Henry addn., elimination/condensation, and rearrangement to the isoxazole.
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Ruider, S. A.; Müller, S.; Carreira, E. M. Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles Angew. Chem., Int. Ed. 2013, 52, 11908– 11911 DOI: 10.1002/anie.201306563
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Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles
Ruider, Stefan A.; Mueller, Steffen; Carreira, Erick M.
Angewandte Chemie, International Edition (2013), 52 (45), 11908-11911CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Spirocycles I (X = O, S, PhN, TsN; R1 = H, Et, Ph, 4-BrC6H4CH2, etc.; R2 = H, Me, i-Pr, n-Bu, Ph, PhCH2, R3 = H; R2 = R3 = Me, Ph; R2R3 = CH2OCMe2OCH2; R4 = H, PhOCH2, R5 = H; R4 = H2C:CH, R5 = Me; etc.) derived from 3-oxetanone and β-heteroatom-substituted amines underwent a Lewis acid mediated reaction cascade with trimethylsilyl cyanide or di-Et trimethylsilyl phosphite to form satd. nitrogen heterocycles II [Y = CN, (EtO)2P(O)]. The unique reactivity of 3-oxetanone facilitates access to biol. important morpholines, piperazines, and thiomorpholines with an otherwise difficult-to-access substitution pattern from readily available starting materials.
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Orr, D.; Tolfrey, A.; Percy, J. M.; Frieman, J.; Harrison, Z. A.; Campbell-Crawford, M.; Patel, V. K. Single-Step Microwave-Mediated Synthesis of Oxazoles and Thiazoles from 3-Oxetanone: A Synthetic and Computational Study Chem. - Eur. J. 2013, 19, 9655– 9662 DOI: 10.1002/chem.201301011
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Single-Step Microwave-Mediated Syntheses of Oxazoles and Thiazoles from 3-Oxetanone: A Synthetic and Computational Study
Orr, David; Tolfrey, Alexandra; Percy, Jonathan M.; Frieman, Joanna; Harrison, Zoe A.; Campbell-Crawford, Matthew; Patel, Vipulkumar K.
Chemistry - A European Journal (2013), 19 (29), 9655-9662CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
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Gold-catalyzed [4+2] cycloaddns. between ynamides and oxetanes was carried out; these reactions involve oxetanes and gold-π-ynamides as nucleophiles and electrophiles, resp. Excellent cycloaddn. regioselectivities are achieved over a reasonable range of ynamide and oxetane substrates. For azetidines, their [4+2] cycloaddns. with ynamides are implemented more efficiently with silver hexafluoroantimonate, which is also compatible with various ynamides and azetidines. These two cycloaddns. provide facile accesses to six-membered heterocycles such as 6-amino-3,4-dihydro-2H-pyrans and 2-amino-1,4,5,6-tetrahydropyridines. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Organic Letters (2014), 16 (6), 1810-1813CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A highly enantioselective chlorination/ring expansion cascade for the construction of cycloalkanones with an all-carbon quaternary center was realized (up to 97% ee). Oxa-cyclobutanol substrates were employed for the first time in the ring expansion reactions, affording the functionalized dihydrofuranones in excellent enantioselectivity.

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Abstract
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Figure 1
Figure 1. Structural properties of oxetane and puckering of the substituted oxetane ring in EDO.
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Figure 2
Figure 2. Oxetane-containing natural products.
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Figure 3
Figure 3. Three proposed pathways for biosynthesis of the oxetane ring of taxol.
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Figure 4
Figure 4. 3,3-Disubstituted oxetanes as replacement group for gem-dimethyl.
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Figure 5
Figure 5. Effects of replacing a gem-dimethyl group with oxetane.
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Figure 6
Figure 6. Effect of oxetane motif on amine basicity.
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Figure 7
Figure 7. Comparison between carbonyl and oxetane functional groups, representing similar arrangement of lone pairs and change in size.
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Figure 8
Figure 8. Examples of oxetanes tested with human liver microsomes and glutathione.
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Figure 9
Figure 9. Matched-pair analysis of logD for 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase.
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Figure 10
Figure 10. Comparison of metabolic stability of N-substituted arylsulfonamides. CL_int,app is total intrinsic clearance obtained from scaling in vitro HLM half-lives.
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Figure 11
Figure 11. Examples from Wessel’s oxetane library.
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Figure 12
Figure 12. Wipf’s oxetane-containing neutral solubilizing group.
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Scheme 1
Scheme 1. Stereocontrolled Synthesis of Oxetanes 19 and 23 from the Corresponding Diols
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Scheme 2
Scheme 2. Asymmetric Synthesis of 2-Aryloxetanes by Use of a Chiral Catalyst
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Scheme 3
Scheme 3. Stereocontrolled Synthesis of Oxetanes from Epoxy Alcohols
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Scheme 4
Scheme 4. Synthesis of Oxetanes 25 and 26 through an Iodination–Williamson Etherification Pathway
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Scheme 5
Scheme 5. (a) Synthesis of the Natural Product Oxetin from d-Glucose and (b) Unnatural Stereoisomers
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Scheme 6
Scheme 6. Synthesis of Oxetanocin by Use of Williamson Etherification for the Key Cyclization Step
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Scheme 7
Scheme 7. Selected Examples of the Oxetane-Forming Step in Taxol Total Syntheses
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Scheme 8
Scheme 8. Solvent-Controlled Synthesis of Cyclopropanes and Oxetane Derivatives from Michael Adducts of Malonates
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Scheme 9
Scheme 9. Selective Synthesis of α-Hydroxymalonates, Cyclopropanes, and Oxetane Derivatives from Michael Adducts
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Scheme 10
Scheme 10. Proposed Mechanism for Conversion to Cyclopropane, α-Hydroxymalonate, and Oxetane Products
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Scheme 11
Scheme 11. Synthesis of Oxetanes via NHC-Catalyzed Formal [2+2] Cycloaddition of Fluorinated Ketones and α-Aroyloxyaldehydes
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Scheme 12
Scheme 12. Synthesis of Oxetan-3-one by Intramolecular Cyclization
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Scheme 13
Scheme 13. Synthesis of 3,3-Disubstituted Oxetanes from Diols
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Scheme 14
Scheme 14. Spirocyclic Building Block 60 and Use in a Ciprofloxacin Analogue
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Scheme 15
Scheme 15. Preparation of Spirocyclic Oxetane Azetidines
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Scheme 16
Scheme 16. Preparation of a Bis-spirocyclic Oxetane Derivative
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Scheme 17
Scheme 17. General Procedure for Synthesis of the Oxetane Ring in Merrilactone A via Payne Rearrangement-type Mechanism
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Scheme 18
Scheme 18. Oxetane Formation through Epoxide Opening with Selenoalkyllithium
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Scheme 19
Scheme 19. Oxetane Formation through Epoxide Opening with Trimethyloxosulfonium Ylide
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Scheme 20
Scheme 20. Asymmetric Synthesis of 2,2-Disubstituted Oxetanes via One-Pot Sequential Addition of Sulfur Ylides to Ketones
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Scheme 21
Scheme 21. Sample Ring Contraction of α-Hydroxy-γ-lactone Triflates
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Scheme 22
Scheme 22. Synthesis of α-Chlorooxetane 78 through Barton Modification of the Hunsdiecker Reaction
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Scheme 23
Scheme 23. Synthesis of Oxetane Nucleoside Analogue from α-Chlorooxetane 78
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Scheme 24
Scheme 24. Synthesis of Triflate Lactones 81–84 from Pentofuranose Sugars
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Scheme 25
Scheme 25. Synthesis of 3-Alkyloxetanes 90 and 92
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Scheme 26
Scheme 26. Synthesis of Oxetanocin and Its α-Epimer
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Scheme 27
Scheme 27. Synthesis of Epinoroxetanocin
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Scheme 28
Scheme 28. Synthesis of Azidooxetanes
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Scheme 29
Scheme 29. Synthesis of Fluorooxetane 107 by Use of Diethylaminosulfur Trifluoride
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Scheme 30
Scheme 30. Synthesis of Oxetanethiol 109
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Scheme 31
Scheme 31. Synthesis of Alkylazidooxetanes
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Scheme 32
Scheme 32. Synthesis of a Protected Amino Acid Oxetane
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Scheme 33
Scheme 33. Hydrolysis of Oxetane Ester by Use of Candida antarctica Lipase L2
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Scheme 34
Scheme 34. Synthesis of Oxetane Hexamer 117
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Scheme 35
Scheme 35. Synthesis of Novel β³-Amino Acids and Penta-α,β-peptide
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Figure 13
Figure 13. Examples of marketed nucleoside antivirals.
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Scheme 36
Scheme 36. Synthesis of Oxetane Nucleoside Phosphoramidite 122 from Ulose 120
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Scheme 37
Scheme 37. Overall Synthetic Strategy for Synthesis of Nucleosides 124a,b
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Scheme 38
Scheme 38. Synthesis of Bicyclic Oxetane 129 from Sugar-Derived Alkene 125
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Figure 14
Figure 14. Structures of 1′,2′-locked oxetane-containing nucleosides 130 and 131.
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Scheme 39
Scheme 39. Synthesis of 1′,2′-Locked Oxetane Nucleoside
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Scheme 40
Scheme 40. Synthesis of Cytosine and Adenine Oxetane-Containing Nucleoside Analogues
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Scheme 41
Scheme 41. Synthesis of Oxetane-Containing Nucleoside Prodrugs
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Scheme 42
Scheme 42. Seven-Step Synthesis of C-4′-Spiro-oxetanoribonucleosides 155 and 156
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Scheme 43
Scheme 43. Synthesis of Adamantyloxetane through NBS-Mediated 4-exo-trig Cyclization
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Scheme 44
Scheme 44. Synthesis of Oxetane-Containing Diterpene Derivative
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Scheme 45
Scheme 45. Synthesis of Iodo-Substituted 2-Alkyloxetanes via 4-exo-trig Cyclization
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Scheme 46
Scheme 46. Synthesis of γ-Secretase Inhibitor 162 via Iodonium-Mediated Oxetane Cyclization
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Scheme 47
Scheme 47. Accessing Oxetanocin A Analogues via Iodonium-Mediated Oxetane Cyclization
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Scheme 48
Scheme 48. Possible Transition States Explaining the Facial Selectivity of Cyclization
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Scheme 49
Scheme 49. Electrophilic Halocyclization of Functionalized Vinylsilanes
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Scheme 50
Scheme 50. Oxetane Synthesis via 4-endo-trig Haloelectrophilic Cyclization^a
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Scheme a(a) Initial result with cinnamic alcohols. (b) Substrate scope accessing highly substituted oxetanes.
Scheme 51
Scheme 51. Synthesis of Oxetane, Tetrahydrofuran, and Tetrahydropyran Rings through Reverse C–O Bond Formation
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Scheme 52
Scheme 52. Au(I)-Catalyzed Cyclization of Propargylic Alcohols to Oxetan-3-ones
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Scheme 53
Scheme 53. Synthesis of Oxetan-3-ones in Two Steps from Allenes
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Scheme 54
Scheme 54. Intramolecular C-Glycosidation Route to Oxetanes
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Scheme 55
Scheme 55. Vinyl Oxetane Formation via Intramolecular Epoxide Ring-Opening Cyclization
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Scheme 56
Scheme 56. Intramolecular Cyclization of Epoxy Ethers Bearing a Benzyl Substituent
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Scheme 57
Scheme 57. Oxetane Formation from Cyclization of Benzyl Epoxides
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Scheme 58
Scheme 58. Regio- and Stereoselective Synthesis of Amino Alcohol-Substituted Oxetanes
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Scheme 59
Scheme 59. Synthesis of Oxetan-3-ones by Intramolecular Ester Condensation
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Scheme 60
Scheme 60. Synthesis of 2-Sulfonyl Oxetanes
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Scheme 61
Scheme 61. Oxetane Synthesis by O–H Insertion/C–C Bond-Forming Cyclization
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Scheme 62
Scheme 62. Synthesis of Functionalized Oxetanes from Unsymmetrical Diazo Compounds
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Scheme 63
Scheme 63. Synthesis of (a) 3-Silyloxyoxetanes and (b) 3-Aminooxetanes via Paternò–Büchi Photochemical [2+2] Cycloadditions
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Scheme 64
Scheme 64. Synthesis of 3,3-Diphenyloxetane by Paternò–Büchi Reaction
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Scheme 65
Scheme 65. Photochemical Reactions of Electron-Poor Alkenyl Boronates with Benzophenone
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Scheme 66
Scheme 66. First Example of Paternò–Büchi Cycloaddition in Flow
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Scheme 67
Scheme 67. Example of Paternò–Büchi Cycloaddition in Flow Compared to Batch Process^a
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Scheme aBooker-Milburn and co-workers. (281)
Scheme 68
Scheme 68. Synthesis of 2-Trifluoromethyloxetanes via Transition Metal-Catalyzed Formal [2+2] Cycloaddition
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Scheme 69
Scheme 69. Synthesis of Chiral, Stable Oxetene Derivatives through Formal [2+2] Cycloaddition Mediated by a Chiral BINAP–Pd Complex
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Scheme 70
Scheme 70. Reduction of Trifluoromethylated Oxetene to the Corresponding Oxetane
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Figure 15
Figure 15. Some commercially available oxetane-containing building blocks.
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Scheme 71
Scheme 71. Synthesis of 3-Amino- and 3-Nitrooxetane
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Scheme 72
Scheme 72. S_N2 Reactions on Simple Oxetane Building Blocks^a
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Scheme aEstrada et al. (288); Sun and co-workers. (289)
Scheme 73
Scheme 73. Synthesis of Two Oxetane Amino Acid Derivatives via Oxetan-3-one
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Scheme 74
Scheme 74. Sample Synthesis of a 3-Aryloxetan-3-ol by Organometallic Addition
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Scheme 75
Scheme 75. Fluorination of Oxetan-3-ol by Use of Diethylaminosulfur Trifluoride
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Scheme 76
Scheme 76. Chlorination of 3-Phenyloxetan-3-ol by Use of Methanesulfonyl Chloride and Triethylamine
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Scheme 77
Scheme 77. Dehydroxylation of Oxetan-3-ols
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Scheme 78
Scheme 78. Preparation of 3-Aminooxetanes by Addition to an Imine^a
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Scheme a(a) Hamzik and Brubaker (350); (b) Ellman and co-workers (351).
Scheme 79
Scheme 79. Nucleophilic Addition of Carbon Nucleophiles onto Spirocyclic Oxetanes
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Scheme 80
Scheme 80. Synthesis of Oxetane Michael Acceptors
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Scheme 81
Scheme 81. Synthesis of 3,3-Diaryloxetanes via Conjugate Addition to Oxetane-Derived α,β-Unsaturated Ester, Aldehyde, and Nitroalkene
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Scheme 82
Scheme 82. Conjugate Addition to Vinyl Sulfone 214 and Reductive Removal
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Scheme 83
Scheme 83. Synthesis of Oxetane-Containing Spirocyclic Compounds Involving Conjugate Addition^a
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Scheme aR = piperonyl.
Scheme 84
Scheme 84. Oxetane-Containing IspE Inhibitor with Improved Aqueous Solubility
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Scheme 85
Scheme 85. Catalytic Enantioselective Synthesis of (a) 1,2-Nitrothioacetates and (b) 1,2-Aminosulfonic Acids
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Scheme 86
Scheme 86. Oxetane Peptidomimetics Formed via Conjugate Addition^a
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Scheme aShipman and co-workers (358); Carreira and co-workers (357).
Scheme 87
Scheme 87. (a) Passerini and (b) Pictet–Spengler Reactions Involving Oxetan-3-one
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Scheme 88
Scheme 88. Inter- and Intramolecular Sydnone Cycloadditions
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Scheme 89
Scheme 89. Synthesis of Spirocyclic Piperazine-Oxetane by Use of SnAP Reagents
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Scheme 90
Scheme 90. Strain-Driven Direct Cross-Aldol Reaction with Oxetan-3-one
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Scheme 91
Scheme 91. Ni-Catalyzed Suzuki Coupling of 3-Iodooxetane^a
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Scheme aDuncton et al. (79)
Scheme 92
Scheme 92. Ni-Catalyzed Suzuki Cross-Coupling Reaction of 3-Iodooxetane and Arylboronic Acids^a
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Scheme aZhang and Yang. (368)
Scheme 93
Scheme 93. Fe-Catalyzed Synthesis of Heteroaryloxetanes from 3-Iodooxetane
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Scheme 94
Scheme 94. Preparation of Oxetane Trifluoroborate
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Scheme 95
Scheme 95. Ni-Catalyzed Reductive Coupling of 3-Bromooxetane
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Scheme 96
Scheme 96. Metal-Free Coupling of Boronic Acids with Saturated Heterocycles by Use of Sulfonyl Hydrazones
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Scheme 97
Scheme 97. Preparation and Indole Coupling Reactions of Oxetane Sulfinate Salts
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Figure 16
Figure 16. Highly potent ALK inhibitors.
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Figure 17
Figure 17. Comparison of metabolic stability of lead compound 229 compared to oxetane-containing analogues. CL_int,app (milliliters per minute per kilogram), shown in parentheses, is total intrinsic clearance obtained from scaling in vitro HLM half-lives.
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Scheme 98
Scheme 98. Preparation of Trifluoromethyl-Substituted Oxetane GPCR119 Agonist
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Figure 18
Figure 18. Potent and selective mTOR inhibitors.
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Figure 19
Figure 19. (a) Inhibitor of LRRK2. (b) Cathespin S inhibitor.
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Scheme 99
Scheme 99. 2,4-Diarylaminopyrimidine Analogues as Potent Inhibitors against Wild-Type and Mutant ALK Kinases
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Scheme 100
Scheme 100. GPCR TGR5 Agonists for Potential Type 2 Diabetes Treatment
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Figure 20
Figure 20. (a) Oxetane-containing hepatitis C virus inhibitor. (b) 3-Sulfonyl oxetane inhibitor of MDM2.
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Figure 21
Figure 21. γ-Secretase modulators with improved metabolic stability.
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Figure 22
Figure 22. Oxetane-containing indazole CCR4 antagonists.
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Figure 23
Figure 23. 4-Azaxanthene BACE1 inhibitors containing a pendent oxetane.
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Figure 24
Figure 24. (a) Oxetane modulating the basicity of H₃R agonists. (b) HIV-1 protease inhibitor. (c) Brain-penetrant 3-methoxy-substituted oxetane PI3K inhibitor. (d) Potent and selective DLK kinase inhibitor.
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Scheme 101
Scheme 101. Large-Scale Preparation of Benzothiazepine RSV Inhibitors
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Scheme 102
Scheme 102. Formation and Reactivity of 2-Lithio-2-phenyloxetane
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Scheme 103
Scheme 103. Functionalization of 2-Arylsulfonyl Oxetanes via Lithation of the Oxetane Ring
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Scheme 104
Scheme 104. Exploiting Ortho-Directing Ability of the Oxetane Ring To Access Functionalized 2-Aryloxetanes
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Scheme 105
Scheme 105. Ortho-Metalation on Pyridine Directed by an Oxetane
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Scheme 106
Scheme 106. Regioselectivity of Alkylation of Oxetane by Use of Decatungstate Photocatalyst
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Scheme 107
Scheme 107. Direct α-Arylation of Ethers by Photoredox Catalysis–Minisci Reaction Sequence
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Scheme 108
Scheme 108. 2-Methyleneoxetanes from Xanthone, Benzaldehyde, and Fluorenone
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Scheme 109
Scheme 109. First Synthesis of 2-Methyleneoxetane 270
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Scheme 110
Scheme 110. Synthesis of 2-Methyleneoxetanes via Intramolecular O-Alkylation of Enolates
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Scheme 111
Scheme 111. Synthesis of 2-Methyleneoxetanes via Methylenation of β-Lactones
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Scheme 112
Scheme 112. Synthesis of 2-Methyleneoxetane Analogue of Orlistat
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Scheme 113
Scheme 113. Synthesis of 2-Methyleneoxetanes through Cu-Catalyzed O-Vinylation
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Scheme 114
Scheme 114. Sample Scope of Cu-Catalyzed Intramolecular Ullman Coupling
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Scheme 115
Scheme 115. Synthesis of 4-Trifluoromethyl-2-methyleneoxetanes via Lewis Base-Catalyzed Formal [2+2] Cycloaddition
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Scheme 116
Scheme 116. Proposed Mechanism for Lewis Base-Catalyzed Formal [2+2] Cycloaddition of Allenoates and 2,2,2-Trifluoroacetophenones
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Scheme 117
Scheme 117. Asymmetric Formal [2+2] Cycloaddition with β-Isocupreidine 285 as Catalyst
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Scheme 118
Scheme 118. Use of TBD as Lewis Base Catalyst for Synthesis of Highly Substituted 2-Alkylideneoxetanes
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Scheme 119
Scheme 119. Tandem Alkene Isomerization/Electrocyclic Ring Opening of 2-Methyleneoxetanes
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Scheme 120
Scheme 120. Epoxidation of 2-Methyleneoxetanes: Synthesis of 1,5-Dioxaspiro[3.2]hexanes
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Scheme 121
Scheme 121. Nucleophilic Ring Opening of 1,5-Dioxaspiro[3.2]hexanes
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Scheme 122
Scheme 122. Synthesis of 2,2-Disubstituted Oxetane 300 by Use of Mg(OTf)₂ and 1,2,4-Triazole
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Scheme 123
Scheme 123. Synthesis of d-erythro-Dihydrosphingosine and d-xylo-Phytosphingosine by Tandem Ring Opening of 1,5-Dioxaspiro[3.2]hexane
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Scheme 124
Scheme 124. Synthesis of epi-Oxetin through DIBAL Opening of 1,5-Dioxaspiro[3.2]hexane^a
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Scheme aBlauvelt and Howell. (477)
Scheme 125
Scheme 125. Unexpected Rearrangement of Oxetane 309 Affording Epoxytetrahydrofuran
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Scheme 126
Scheme 126. Synthesis of [2.2.0]-Fused Ketal
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Scheme 127
Scheme 127. Synthesis of Oxetane-Containing psico-Nucleosides
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Scheme 128
Scheme 128. Cyclopropanation of 2-Methyleneoxetanes To Form 2-Oxaspiro[2.3]hexanes
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Scheme 129
Scheme 129. Rearrangement of 4-Oxaspirohexanes Catalyzed by BF₃·Et₂O
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Scheme 130
Scheme 130. Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans via Platinacyclobutane Intermediate
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Scheme 131
Scheme 131. Ring Opening of Oxetanes by Attack of an Isonitrile Nucleophile
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Scheme 132
Scheme 132. Ring Opening of 2-Aryloxetanes with Aryl Borates
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Scheme 133
Scheme 133. Intramolecular Opening of Substituted Oxetanes with Alkyl Hydroperoxides
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Scheme 134
Scheme 134. Fe-Catalyzed Reductive Magnesiation of 2-Phenyloxetane
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Scheme 135
Scheme 135. Formation of Primary Alcohols by Ring Opening of Oxetanes
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Scheme 136
Scheme 136. Rh-Catalyzed C-Carbamoylation of Oxetanols and Isocyanates
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Scheme 137
Scheme 137. Oxetane Ring Opening in Total Synthesis of (±)-Gelsemine^a
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Scheme aDanishefsky and co-workers. (512, 513)
Scheme 138
Scheme 138. Intramolecular Cyclization to Dihydrobenzofuran or Benzofuran Derivatives
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Scheme 139
Scheme 139. Synthesis of Bis-Spirocycles through Paternò–Büchi Reaction and Acid-Promoted Intramolecular Cyclization
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Scheme 140
Scheme 140. Oxetane Ring-Opening Step in Total Synthesis of Ascospiroketal
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Scheme 141
Scheme 141. Enantioselective Ring Opening of 3-Substituted Oxetanes with Stoichiometric Chiral Ligand
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Scheme 142
Scheme 142. Enantioselective Ring Opening of 3-Substituted Oxetanes with Mercaptobenzothiazoles
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Scheme 143
Scheme 143. Co-Catalyzed Intramolecular Ring Opening of 3-Substituted Oxetanes
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Scheme 144
Scheme 144. Asymmetric Ring Opening of 3-Substituted Oxetanes by Use of Aromatic Amines and Chiral Phosphoric Acid Catalyst
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Scheme 145
Scheme 145. Enantioselective Synthesis of Alternative Oxaheterocycles
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Scheme 146
Scheme 146. Cascade Formation of Isoxazoles by Rearrangement of Oxetanes
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Scheme 147
Scheme 147. Asymmetric Ring Expansion of 2-Aryloxetanes by Use of Cu(I)/Bis(azaferrocene) Catalyst
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Scheme 148
Scheme 148. Macrocyclization of Oxetanes with α-Diazo-β-keto Esters
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Scheme 149
Scheme 149. Synthesis of 1,3-Oxazines via Cycloaddition of Vinyloxetanes with Isocyanates or Carbodiimides
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Scheme 150
Scheme 150. Ring Expansion of Vinyloxetanes to Medium-Sized Oxacycles
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Scheme 151
Scheme 151. Ring Expansion of Vinyloxetanes to 3,6-Dihydro-2H-pyrans
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Scheme 152
Scheme 152. Z-Selective Ring Opening and Ring Expansion of Vinyloxetanes
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Scheme 153
Scheme 153. Nickel-Catalyzed Cycloaddition of 1,3-Dienes with Oxetan-3-ones and Azetidin-3-ones
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Scheme 154
Scheme 154. Au- and Ag-Catalyzed [4 + 2] Cycloaddition of Ynamides with Oxetanes^a
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Scheme aL = (o-biphenyl)(t-Bu)₂P.
Scheme 155
Scheme 155. Asymmetric Chlorination/Ring Expansion of Oxetanols
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References
This article references 551 other publications.
1. 1
  Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Carreira, E. M. Oxetanes as Versatile Elements in Drug Discovery and Synthesis Angew. Chem., Int. Ed. 2010, 49, 9052– 9067 DOI: 10.1002/anie.200907155
  1
  Oxetanes as Versatile Elements in Drug Discovery and Synthesis
  Burkhard, Johannes A.; Wuitschik, Georg; Rogers-Evans, Mark; Mueller, Klaus; Carreira, Erick M.
  Angewandte Chemie, International Edition (2010), 49 (48), 9052-9067CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compds. often encounter difficulties in satisfying and overcoming the numerous physicochem. and many pharmacol. constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto mol. scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a mol. scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the prepn. and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochem. and biochem. properties that result from the incorporation of the oxetane unit in mol. architectures.
2. 2
  Carreira, E. M.; Fessard, T. C. Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities Chem. Rev. 2014, 114, 8257– 8322 DOI: 10.1021/cr500127b
  2
  Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities
  Carreira, Erick M.; Fessard, Thomas C.
  Chemical Reviews (Washington, DC, United States) (2014), 114 (16), 8257-8322CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. The objective of this review is to provide an up-to-date survey of spirocyclic structures contg. at least one four-membered ring. For example, the authors state that a broad search for reported spirocyclic structures in spiro[3.3]-, spiro[3.4]- and spiro[3.5]-alkane classes produces results that exceed 2 million. The structures are equally divided in each of the three categories of spiro[3.3]heptanes, spiro[3.4]octanes and spiro[3.5]nonanes. The authors have limited the scope of this review to mols. which include only four-membered ring-contg. spiro(carbo and hetero)cycles. This review underscores the need for the development of synthetic routes to numerous substituted congeners of the various spirocycles where great opportunities bound.
3. 3
  Abe, M. Recent Progress Regarding Regio-, Site-, and Stereoselective Formation of Oxetanes in Paternò-Büchi Reactions J. Chin. Chem. Soc. 2008, 55, 479– 486 DOI: 10.1002/jccs.200800072
  3
  Recent progress regarding regio-, site-, and stereoselective formation of oxetanes in Paterno-Buechi reactions
  Abe, Manabu
  Journal of the Chinese Chemical Society (Taipei, Taiwan) (2008), 55 (3), 479-486CODEN: JCCTAC; ISSN:0009-4536. (Chinese Chemical Society)
  A review. Recently, the demand for synthetic oxetanes has increased because the highly strained structure allows specific biol. functions in vivo and also serves unique purposes in industrial materials. This review article summarizes recent progress in regio-, site-, and stereo-selective formation of oxetanes via a photochem. process.
4. 4
  D’Auria, M.; Racioppi, R. Oxetane Synthesis Through the Paternò-Büchi Reaction Molecules 2013, 18, 11384– 11428 DOI: 10.3390/molecules180911384
  4
  Oxetane synthesis through the Paterno-Buchi reaction
  D'Auria, Maurizio; Racioppi, Rocco
  Molecules (2013), 18 (9), 11384-11428CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  A review. The Paterno-Buchi reaction is a photochem. reaction between a carbonyl compd. and an alkene to give the corresponding oxetane. The reaction mechanism is discussed and reaction with electron rich alkenes (enolethers, enol esters, enol silyl ethers, enamines, heterocyclic compds.) has been reported. The stereochem. behavior of the reaction is particularly stressed. The reported applications of this reaction to the synthesis of naturally occurring compds is also discussed.
5. 5
  Dejaegher, Y.; Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe, N. The Chemistry of Azetidin-3-ones, Oxetan-3-ones, and Thietan-3-ones Chem. Rev. 2002, 102, 29– 60 DOI: 10.1021/cr990134z
  5
  The Chemistry of Azetidin-3-ones, Oxetan-3-ones, and Thietan-3-ones
  Dejaegher, Yves; Kuz'menok, Nina M.; Zvonok, Alexander M.; De Kimpe, Norbert
  Chemical Reviews (Washington, D. C.) (2002), 102 (1), 29-60CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review with 254 refs.
6. 6
  Mahal, A. Oxetanes as Versatile Building Blocks in the Total Synthesis of Natural Products: An Overview Eur. J. Chem. 2015, 6, 357– 366 DOI: 10.5155/eurjchem.6.3.357-366.1267
  6
  Oxetanes as versatile building blocks in the total synthesis of natural products: an overview
  Mahal, Ahmed
  European Journal of Chemistry (2015), 6 (3), 357-366CODEN: EJCUA9; ISSN:2153-2249. (European Journal of Chemistry)
  A review. Oxetane ring plays an important role as main core in naturally occurring compds. and has many applications in pharmaceutical industries and synthetic org. chem. In this review, we report a brief survey of using the oxetane ring as versatile precursors in the total synthesis of natural products. Many approaches such as cyclization, addn., oxidn., redn., elimination, protection as well as deprotection reactions utilized to synthesize of most important oxetane-contg. natural products involving taxol, (±)-merrilactone A, (±)-oxetin, L-oxetanocin, (+)-(Z)-laureatin and L-oxetanocin are also covered. We describe in this review the most common total synthesis approaches have been yet applied to synthesis of most important oxetane-contg. natural products. The review is also included isolation, structure identification of these oxetane-contg. natural products. The biol. activity of oxetane-contg. natural products due to the oxetane ring is also defined.
7. 7
  Malapit, C. A.; Howell, A. R. Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds J. Org. Chem. 2015, 80, 8489– 8495 DOI: 10.1021/acs.joc.5b01255
  7
  Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds
  Malapit, Christian A.; Howell, Amy R.
  Journal of Organic Chemistry (2015), 80 (17), 8489-8495CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A review. Oxetanes are valuable intermediates in org. synthesis, and strategic manipulations of this strained heterocycle continue to emerge. In this Synopsis, recent, distinct approaches to construct heterocyclic systems using oxetanes are described. These include ring expansion, ring opening, and C-2 functionalization.
8. 8
  Wang, Z.; Chen, Z.; Sun, J. Catalytic Asymmetric Nucleophilic Openings of 3-Substituted Oxetanes Org. Biomol. Chem. 2014, 12, 6028– 6032 DOI: 10.1039/C4OB00920G
  8
  Catalytic asymmetric nucleophilic openings of 3-substituted oxetanes
  Wang, Zhaobin; Chen, Zhilong; Sun, Jianwei
  Organic & Biomolecular Chemistry (2014), 12 (32), 6028-6032CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A review. Asym. ring-opening of 3-substituted oxetanes provides rapid access to highly functionalized chiral building blocks. However, progress in this field is limited. Recently the authors developed a new catalytic system based on chiral Bronsted acids for this type of reaction and demonstrated the synthesis of a range of useful mols. under mild and operationally simple conditions. In this perspective, the authors describe the challenges, progress, and potential future efforts on this topic.
9. 9
  Hailes, H. C.; Behrendt, J. M. Oxetanes and Oxetenes: Monocyclic. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K., 2008; Vol. 2, Chapt. 2.05, pp 321– 364; DOI: DOI: 10.1016/B978-008044992-0.00205-4 .
  There is no corresponding record for this reference.
10. 10
  Dussault, P. H.; Xu, C. Oxetanes and Oxetenes: Fused-ring Derivatives. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K., 2008; Vol. 2, Chapt. 2.06, pp 365– 387; DOI: DOI: 10.1016/B978-008044992-0.00206-6 .
  There is no corresponding record for this reference.
11. 11
  Alcaide, B.; Almendros, P. Four-Membered Ring Systems. In Progress in Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A., Eds.; Elsevier: New York, 2011; Vol. 23, Chapt. 4, pp 101– 125; DOI: DOI: 10.1016/B978-0-08-096805-6.00004-8 .
  There is no corresponding record for this reference.
12. 12
  Kudo, H.; Nishikubo, T. Catalytic Reactions of Oxetanes with Protonic Reagents and Aprotic Reagents Leading to Novel Polymers J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 709– 726 DOI: 10.1002/pola.21828
  12
  Catalytic reactions of oxetanes with protonic reagents and aprotic reagents leading to crosslinked and hyperbranched polymers
  Kudo, Hiroto; Nishikubo, Tadatomi
  Journal of Polymer Science, Part A: Polymer Chemistry (2007), 45 (5), 709-726CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
  A review. This paper reports new addn. reactions of oxetanes with certain protonic reagents such as carboxylic acid, phenol, and thiol, and with certain aprotic reagents such as acyl chloride, thioester, phosphonyl dichloride, silyl chloride, and chloroformate using quaternary onium salts as catalysts. The kinetic study of the addn. reactions of oxetanes was also studied. These new addn. reactions were applicable to the synthesis of new polymers. These polyaddn. systems could also construct both polymer main chains and reactive side chains. The alternating copolymn. of oxetanes with carboxylic anhydride was performed. Also, anionic ring-opening polymn. of oxetanes contg. hydroxy groups proceeded to afford the hyperbranched polymer (HBP) with an oxetanyl group and many hydroxy groups at the ends of the polymer chains. Alkali-developable photofunctional HBPs were synthesized by the polyaddn. of bis(oxetane)s or tris(oxetane)s, and their patterning properties were examd., too. The photo-induced cationic polymn. of the polymers with pendant oxetanyl groups and the thermal curing reactions of poly-functional oxetanes (oxetane resins) were also examd. to give the crosslinking materials quant.
13. 13
  Schulte, B.; Dannenberg, C. A.; Keul, H.; Moeller, M. Formation of Linear and Cyclic Polyoxetanes in the Cationic Ring-Opening Polymerization of 3-Allyloxymethyl-3-Ethyloxetane and Subsequent Postpolymerization Modification of poly(3-Allyloxymethyl-3-Ethyloxetane) J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 1243– 1254 DOI: 10.1002/pola.26494
  13
  Formation of linear and cyclic polyoxetanes in the cationic ring-opening polymerization of 3-allyloxymethyl-3-ethyloxetane and subsequent postpolymerization modification of poly(3-allyloxymethyl-3-ethyloxetane)
  Schulte, Bjoern; Dannenberg, Carl A.; Keul, Helmut; Moeller, Martin
  Journal of Polymer Science, Part A: Polymer Chemistry (2013), 51 (5), 1243-1254CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
  The synthesis of 3-allyloxymethyl-3-ethyloxetane (AllylEHO) and its polymn. with BF3 × Et2O is described in this study. Size exclusion chromatog. (SEC) and membrane osmometry are used for the detn. of mol. wts. of the obtained products, ranging from Mn,SEC = 41,500-131,500 g/mol. 1H NMR spectroscopy, SEC, as well as MALDI-TOF MS reveal the formation of cyclic tetramer beside low, but detectable concns. of larger cyclic oligomers as byproducts during the polymn. process. These results help to understand mechanistically why attempts for a controlled homopolymn. of AllylEHO fail and why a controlled homopolymn. of oxetanes has not been described so far in the literature. Addnl., the high versatility of allyl-functional polyoxetane for postpolymn. modification is proven by thiol-ene reactions with 3-mercaptopropionic acid and N-acetyl-L-cysteine Me ester. cpr 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012.
14. 14
  Christ, E. M.; Müller, S. S.; Berger-Nicoletti, E.; Frey, H. Hydroxyfunctional Oxetane-Inimers with Varied Polarity for the Synthesis of Hyperbranched Polyether Polyols via Cationic ROP J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2850– 2859 DOI: 10.1002/pola.27315
  14
  Hydroxyfunctional oxetane-inimers with varied polarity for the synthesis of hyperbranched polyether polyols via cationic ROP
  Christ, Eva-Maria; Mueller, Sophie S.; Berger-Nicoletti, Elena; Frey, Holger
  Journal of Polymer Science, Part A: Polymer Chemistry (2014), 52 (19), 2850-2859CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
  Synthesis and characterization of novel hydroxyl-functionalized oxetane-inimers with varied alkyl chain length-3-hydroxymethyl-3-methoxymethyloxetane, 3-hydroxymethyl-3-propoxymethyloxetane, and 3-hexyloxymethyl-3-hydroxymethyloxetane-is reported. Cationic ring-opening polymn. of these latent, cyclic AB2-monomers leads to hyperbranched (hb) polyether polyols with degrees of branching between 34 and 69%, confirmed by inverse-gated (IG) 13C NMR spectroscopy. The hyperbranching polymn. yielded apparent mol. wts. (Mn) ranging from 500 to 2500 g mol-1 (size exclusion chromatog.). Remarkably, by copolymn. of 1,1,1-tris(4-hydroxyphenyl)ethane as a "focal" unit, polymn. under slow monomer addn. conditions lead to higher apparent mol. wts. up to 11,220 g mol-1. The end groups of the hb polymers were studied via matrix-assisted laser desorption/ionization time of flight mass and NMR spectrometry. By varying the alkyl chain length, tailoring of the soly. and glass transition temps. of the materials is possible. Potential applications range from macroinitiators with defined polarity to tailoring of surface properties of antifouling materials. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014.
15. 15
  Schulte, B.; Rahimi, K.; Keul, H.; Demco, D. E.; Walther, A.; Möller, M. Blending of Reactive Prepolymers to Control the Morphology and Polarity of Polyglycidol Based Microgels Soft Matter 2015, 11, 943– 953 DOI: 10.1039/C4SM02116A
  There is no corresponding record for this reference.
16. 16
  Kudo, H.; Morita, A.; Nishikubo, T. Synthesis of a Hetero Telechelic Hyperbranched Polyether. Anionic Ring-Opening Polymerization of 3-Ethyl-3-(hydroxymethyl)oxetane Using Potassium tert-Butoxide as an Initiator Polym. J. 2003, 35, 88– 91 DOI: 10.1295/polymj.35.88
  16
  Synthesis of a hetero telechelic hyperbranched polyether. Anionic ring-opening polymerization of 3-ethyl-3-(hydroxymethyl)oxetane using potassium tert-butoxide as an initiator
  Kudo, Hiroto; Morita, Ayako; Nishikubo, Tadatomi
  Polymer Journal (Tokyo, Japan) (2003), 35 (1), 88-91CODEN: POLJB8; ISSN:0032-3896. (Society of Polymer Science, Japan)
  The anionic ring-opening polymn. of 3-ethyl-(3-hydroxymethyl)oxetane (EHO) affording hetero telechelic hyperbranched polyethers contg. an oxetanyl and many OH-groups at the ends (poly(EHO)) is described. Polymn. of EHO was performed in presence of t-BuOK and 18-crown-6 in N-methylpyrrolidone. Polymn. outcome was detd. in dependence of reaction time and temp. (24, 48, and 168 h; 100, 120, 140, 160, 180°). The structure of dendritic poly(EHO) was elucidated and thermal properties were detd.
17. 17
  Morita, A.; Kudo, H.; Nishikubo, T. Synthesis of Hyperbranched Polymers by the Anionic Ring-Opening Polymerization of 3,3-Bis(hydroxymethyl)oxetane Polym. J. 2004, 36, 413– 421 DOI: 10.1295/polymj.36.413
  17
  Synthesis of hyperbranched polymers by the anionic ring-opening polymerization of 3,3-bis(hydroxymethyl)oxetane
  Morita, Ayako; Kudo, Hiroto; Nishikubo, Tadatomi
  Polymer Journal (Tokyo, Japan) (2004), 36 (5), 413-421CODEN: POLJB8; ISSN:0032-3896. (Society of Polymer Science, Japan)
  The anionic ring-opening polymn. of 3,3-bis(hydroxymethyl)oxetane (BHO) was carried out using t-BuOK as an initiator in the presence of 18-crown-6-ether (18-C-6) in NMP at 180 °C, affording the corresponding hyperbranched polyethers, poly(BHO)s contg. an oxetanyl group and many hydroxyl groups at the ends in 83-98% yields. Since the resulting poly(BHO)s were insol. in common org. solvents, the poly(BHO)s were treated with acetic anhydride to obtain poly(BHO-Ac)s contg. acetyl groups at the ends. The Mns and degree of branching (DB) of poly(BHO-Ac)s were in the range of 2600-4400 estd. by SEC and 0.09-0.55 calcd. by 13C NMR spectroscopy, resp. The cationic copolymn. of poly(BHO-Ac) and 3-ethyl-3-phenoxymethyloxetane (EPO) was examd. using BF3OEt2 as an initiator in CHCl3 at 0 °C for 24 h, affording pseudo dendritic polymers, poly-[poly(BHO-Ac)/EPO]s with Mn = 11000-15000 in 58-65% yields. Furthermore, the obtained poly[poly(BHO-Ac)/EPO] was hydrolyzed with KOH to afford the poly[poly(BHO)/EPO] contg. many hydroxyl groups.
18. 18
  Crivello, J. V. Kick-Starting” Oxetane Photopolymerizations J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2934– 2946 DOI: 10.1002/pola.27329
  18
  "Kick-Starting" oxetane photopolymerizations
  Crivello, James V.
  Journal of Polymer Science, Part A: Polymer Chemistry (2014), 52 (20), 2934-2946CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
  In the presence of small amts. of 2,2-dialkyl-, 2,2,3-trialkyl-, or 2,2,3,3-tetraalkyl substituted epoxides such as isobutylene oxide, 1,2-limonene oxide, and 2,2,3,3,-tetramethyloxirane, the photoinitiated cationic ring-opening polymns. of 3,3-disubstituted oxetanes are dramatically accelerated. The acceleration affect was attributed to an increase in the rate of the initiation step of these latter monomers. Both mono- and disubstituted oxetane monomers are similarly accelerated by the above-mentioned epoxides to give crosslinked network polymers. The potential for the use of such "kick-started" systems in applications such as coatings, adhesives, printing inks, dental composites and in three-dimensional imaging is discussed. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014.
19. 19
  Ghosh, B.; Urban, M. W. Self-Repairing Oxetane-Substituted Chitosan Polyurethane Networks Science 2009, 323, 1458– 1460 DOI: 10.1126/science.1167391
  19
  Self-Repairing Oxetane-Substituted Chitosan Polyurethane Networks
  Ghosh, Biswajit; Urban, Marek W.
  Science (Washington, DC, United States) (2009), 323 (5920), 1458-1460CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Polyurethanes have many properties that qualify them as high-performance polymeric materials, but they still suffer from mech. damage. We report the development of polyurethane networks that exhibit self-repairing characteristics upon exposure to UV light. The network consists of an oxetane-substituted chitosan precursor incorporated into a two-component polyurethane. Upon mech. damage of the network, four-member oxetane rings open to create two reactive ends. When exposed to UV light, chitosan chain scission occurs, which forms crosslinks with the reactive oxetane ends, thus repairing the network. These materials are capable of repairing themselves in less than an hour and can be used in many coatings applications, ranging from transportation to packaging or fashion and biomedical industries.
20. 20
  Müller, S. S.; Frey, H. Synthesis of Oxetane-Functional Aliphatic Polyesters via Enzymatic Polycondensation Macromol. Chem. Phys. 2012, 213, 1783– 1790 DOI: 10.1002/macp.201200269
  There is no corresponding record for this reference.
21. 21
  Baba, A.; Kashiwagi, H.; Matsuda, H. Reaction of Carbon Dioxide with Oxetane Catalyzed by Organotin Halide Complexes: Control of Reaction by Ligands Organometallics 1987, 6, 137– 140 DOI: 10.1021/om00144a024
  21
  Reaction of carbon dioxide with oxetane catalyzed by organotin halide complexes: control of reaction by ligands
  Baba, Akio; Kashiwagi, Hiroki; Matsuda, Haruo
  Organometallics (1987), 6 (1), 137-40CODEN: ORGND7; ISSN:0276-7333.
  Complexes of organotin iodides with phosphines or phosphine oxides catalyze the addn. of CO2 to oxetane (I), giving trimethylene carbonate (II) and polycarbonate (III). The choice of a ligand is crucial. All the complexes with Bu3P gave III; the combination of Bu3SnI with Bu3P(O) gave II exclusively in good yields. The complex, Bu2SnI2·Bu3P(O), had no catalytic activity in the formation of either II or III from I. The coordination mode of ligands and the stability of the complexes are important. The function of ligands involves not only activation of the Sn/halogen bond but also the decrease in the acidity of the Sn compds., thus suppressing polymns.
22. 22
  Darensbourg, D. J.; Moncada, A. I. (Salen)Co(II)/n-Bu₄NX Catalysts for the Coupling of CO₂ and Oxetane: Selectivity for Cyclic Carbonate Formation in the Production of Poly-(trimethylene Carbonate) Macromolecules 2009, 42, 4063– 4070 DOI: 10.1021/ma9002006
  22
  (Salen)Co(II)/n-Bu4NX Catalysts for the Coupling of CO2 and Oxetane: Selectivity for Cyclic Carbonate Formation in the Production of Poly(trimethylene carbonate)
  Darensbourg, Donald J.; Moncada, Adriana I.
  Macromolecules (Washington, DC, United States) (2009), 42 (12), 4063-4070CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
  The (salen)Co(II) complex ((1R,2R)-(-)-1,2-cyclohexanediamino-N,N'-bis(3,5-di-tert-butylsalicylidene)cobalt(II)) in the presence of an anion initiator, e.g. bromide, was a effective catalytic system for the coupling of oxetane and carbon dioxide, to provide the corresponding polycarbonate with minimal amt. of ether linkages. The mechanism of the coupling of oxetane and carbon dioxide was studied by in situ IR spectroscopy, where the first formed product is trimethylene carbonate (TMC). TMC is formed by a backbiting mechanism following ring-opening of oxetane by the anion initiator, subsequent to CO2 insertion into the cobalt-oxygen bond. The formation of the copolymer is shown to proceed mostly by way of the anionic ring-opening polymn. of preformed trimethylene carbonate in the presence of an anion in soln. Anions that are good leaving groups, i.e., bromide and iodide, are most effective at affording copolymer via this route. In the presence of greater than 2 equiv of anions the overall rate of copolymer prodn. is decreased, presumably due to inhibition of oxetane monomer binding to the cobalt center. However, under these conditions copolymer formation through ROP of TMC is enhanced, with mass spectral evidence found for the formation of a dimer of TMC.
23. 23
  Darensbourg, D. J.; Horn, A., Jr; Moncada, A. I. A Facile Catalytic Synthesis of Trimethylene Carbonate from Trimethylene Oxide and Carbon Dioxide Green Chem. 2010, 12, 1376– 1379 DOI: 10.1039/c0gc00136h
  23
  A facile catalytic synthesis of trimethylene carbonate from trimethylene oxide and carbon dioxide
  Darensbourg, Donald J.; Horn, Adolfo, Jr.; Moncada, Adriana I.
  Green Chemistry (2010), 12 (8), 1376-1379CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
  The coupling of oxetane (trimethylene oxide) and carbon dioxide catalyzed by VO(acac)2 in the presence of an onium salt was studied. The process is highly selective and quant. for the prodn. of the six-membered cyclic carbonate, trimethylene carbonate, under very mild reaction conditions of 60 °C and 1.7 MPa. Other derivs. of trimethylene oxide similarly selectively afford the corresponding cyclic carbonates upon reaction with CO2.
24. 24
  Buckley, B. R.; Patel, A. P.; Wijayantha, K. G. U. Selective Formation of Trimethylene Carbonate (TMC): Atmospheric Pressure Carbon Dioxide Utilization Eur. J. Org. Chem. 2015, 2015, 474– 478 DOI: 10.1002/ejoc.201403385
  24
  Selective Formation of Trimethylene Carbonate (TMC): Atmospheric Pressure Carbon Dioxide Utilization
  Buckley, Benjamin R.; Patel, Anish P.; Upul Wijayantha, K. G.
  European Journal of Organic Chemistry (2015), 2015 (3), 474-478CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Carbon dioxide utilization (CDU) is currently gaining increased interest due to the abundance of CO2 and its possible application as a C1 building block. We herein report the first example of atm. pressure carbon dioxide incorporation into oxetane to selectively form trimethylene carbonate (TMC), which is a significant challenge as TMC is thermodynamically less favored than its corresponding co-polymer.
25. 25
  Whiteoak, C. J.; Martin, E.; Belmonte, M. M.; Benet-Buchholz, J.; Kleij, A. W. An Efficient Iron Catalyst for the Synthesis of Five- and Six-Membered Organic Carbonates under Mild Conditions Adv. Synth. Catal. 2012, 354, 469– 476 DOI: 10.1002/adsc.201100752
  25
  An Efficient Iron Catalyst for the Synthesis of Five- and Six-Membered Organic Carbonates under Mild Conditions
  Whiteoak, Christopher J.; Martin, Eddy; Belmonte, Marta Martinez; Benet-Buchholz, Jordi; Kleij, Arjan W.
  Advanced Synthesis & Catalysis (2012), 354 (2-3), 469-476CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An iron(III) amine triphenolate complex, [FeTPhOA]2, able to efficiently catalyze the cycloaddn. of carbon dioxide to a range of terminal epoxides under mild conditions, is described. In addn., it has also been found that the complex is able to catalyze the conversion with more sterically congested oxiranes and oxetanes which are generally considered challenging substrates to activate. Variation of the co-catalyst, required for ring-opening of the substrates, has also been examd. The results show that terminal epoxide substrates are converted more efficiently with an iodide co-catalyst, whereas more bulky oxirane substrates give better product yields in the presence of a bromide co-catalyst. The combined results demonstrate the broad applicability of these iron(III) complexes in this type of carbon dioxide fixation chem.
26. 26
  Rintjema, J.; Guo, W.; Martin, E.; Escudero-Adán, E. C.; Kleij, A. W. Highly Chemoselective Catalytic Coupling of Substituted Oxetane and Carbon Dioxide Chem. - Eur. J. 2015, 21, 10754– 10762 DOI: 10.1002/chem.201501576
  26
  Highly Chemoselective Catalytic Coupling of Substituted Oxetanes and Carbon Dioxide
  Rintjema, Jeroen; Guo, Wusheng; Martin, Eddy; Escudero-Adan, Eduardo C.; Kleij, Arjan W.
  Chemistry - A European Journal (2015), 21 (30), 10754-10762CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An effective method for the synthesis of six-membered cyclic carbonates relying on the use of Al catalysis is described. The catalytic reactions can be carried out with excellent selectivity for the cyclic carbonate product tolerating various (functional) groups present in the 2- and 3-position(s) of the oxetane ring. The presented methodol. is the first general approach towards the formation of six-membered cyclic carbonates (6MCCs) through oxetane/CO2 coupling chem. Apart from a series of substituted six-membered cyclic carbonates e.g., I, also the unprecedented room-temp. coupling of oxetanes and CO2 is disclosed giving, depending on the structural features of the substrate, a variety of five- and six-membered heterocyclic products. A mechanistic rationale is presented for their formation and support for the intermediary presence of a carbonic acid deriv. is given. The presented functional carbonates may hold great promise as building blocks in org. synthesis and the development of new, biodegradable polymers.
27. 27
  Guo, W.; Laserna, V.; Rintjema, J.; Kleij, A. W. Catalytic One-Pot Oxetane to Carbamate Conversions: Formal Synthesis of Drug Relevant Molecules Adv. Synth. Catal. 2016, 358, 1602– 1607 DOI: 10.1002/adsc.201500895
  27
  Catalytic One-Pot Oxetane to Carbamate Conversions: Formal Synthesis of Drug Relevant Molecules
  Guo, Wusheng; Laserna, Victor; Rintjema, Jeroen; Kleij, Arjan W.
  Advanced Synthesis & Catalysis (2016), 358 (10), 1602-1607CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Oxetanes are versatile building blocks in drug-related synthesis to induce property-modulating effects. Whereas related oxiranes are widely used in coupling chem. with CO2 to afford value-added commodity chems., oxetane/CO2 couplings remain extremely limited despite the recent advances in the synthesis of these four-membered heterocycles. Here we report an effective one-pot three-component reaction (3CR) strategy for the coupling of (substituted) oxetanes, amines, and CO2 to afford a variety of functionalized carbamates with excellent chemoselectivity and good yields. The process is mediated by an aluminum-based catalyst under relatively mild conditions and the developed catalytic methodol. can be applied to the formal synthesis of two pharmaceutically relevant carbamates with the 3CR being a key step.
28. 28
  Charas, A.; Morgado, J. Oxetane-functionalized Conjugated Polymers in Organic (Opto)Electronic Devices Curr. Phys. Chem. 2012, 2, 241– 264 DOI: 10.2174/1877946811202030241
  28
  Oxetane-functionalized conjugated polymers in organic (opto)electronic devices
  Charas, Ana; Morgado, Jorge
  Current Physical Chemistry (2012), 2 (3), 241-264CODEN: CPCUBU; ISSN:1877-9468. (Bentham Science Publishers Ltd.)
  A review π-Conjugated polymers have found applications as active materials in a range of optoelectronic devices due to being intrinsically semiconducting, exhibiting switchable properties in the course of redox processes, and the possibility of being processed from soln. Current developments in mol. design have been extended to include switchable soly. by means of chem. crosslinking via polymn. of photo-reactive groups attached to the polymer backbone. Exploiting the cross-linkable ability of conjugated polymers has allowed extending applications to multilayered devices fabrication, as the cross-linked structure does not re-dissolve upon further deposition of solns., and also to patterning processes, at the sub-micrometric scale, based on photo-induced methods (photo-lithog.) or on phase-sepn. in spin cast polymer blends. Among the classes of cross-linkable conjugated polymers, those contg. oxetane units as the crosslinking moiety have been the most explored in terms of applications in optoelectronic devices. In this article, we review the recent progress in the field of oxetane-functionalized conjugated polymers, focusing on their mol. design to control electronic and processing properties and their most relevant applications in org. electronics.
29. 29
  Crivello, J. V. Aryl Epoxides as Accelerators for the Photopolymerization of Oxetane Monomers J. Macromol. Sci., Part A: Pure Appl.Chem. 2015, 52, 336– 344 DOI: 10.1080/10601325.2015.1018803
  29
  Aryl Epoxides as Accelerators for the Photopolymerization of Oxetane Monomers
  Crivello, James V.
  Journal of Macromolecular Science, Part A: Pure and Applied Chemistry (2015), 52 (5), 336-344CODEN: JSPCE6; ISSN:1060-1325. (Taylor & Francis, Inc.)
  Epoxides bearing aryl groups function as "kick-starters" to markedly accelerate the photoinitiated cationic ring-opening polymn. of oxetane monomers. Thus, it has been obsd. that the inclusion of a small amt. of styrene oxide transforms a sluggishly polymg. 3-mono- or 3,3-disubstituted oxetane monomer into one that undergoes rapid, exothermic polymn. Mechanistic studies suggest that the activity of aryl epoxides as "kick-starters" is related to their ability to intercept photogenerated acids to form benzylic cations that rapidly initiate oxetane monomer polymn. by alkylation of the monomer.
30. 30
  Tsutsumi, H.; Suzuki, A. Cross-Linked Poly(oxetane) Matrix for Polymer Electrolyte Containing Lithium Ions Solid State Ionics 2014, 262, 761– 764 DOI: 10.1016/j.ssi.2013.09.049
  There is no corresponding record for this reference.
31. 31
  Pell, A. S.; Pilcher, G. Measurements of Heats of Combustion by Flame Calorimetry. Part 3. - Ethylene Oxide, Trimethylene Oxide, Tetrahydrofuran and Tetrahydropy Trans. Faraday Soc. 1965, 61, 71– 77 DOI: 10.1039/TF9656100071
  There is no corresponding record for this reference.
32. 32
  Eigenmann, H. K.; Golden, D. M.; Benson, S. W. Revised Group Additivity Parameters for the Enthalpies of Formation of Oxygen-Containing Organic Compounds J. Phys. Chem. 1973, 77, 1687– 1691 DOI: 10.1021/j100632a019
  32
  Revised group additivity parameters for the enthalpies of formation of oxygen-containing organic compounds
  Eigenmann, H. K.; Golden, D. M.; Benson, S. W.
  Journal of Physical Chemistry (1973), 77 (13), 1687-91CODEN: JPCHAX; ISSN:0022-3654.
  Data on ΔH f°, the std. enthalpies of formation in the gas phase for over 300 O-contg. compds. are critically examd. Internal consistencies within this set are scrutinized from the viewpoint of group additivity principles. New values for the contributions of groups to ΔHf°, as well as higher order corrections, are obtained from multilinear regression anal. of the data. For alcs. and ethers obsd. values and group additivity values agree to within ±1.0 kcal/mole, which is about the exptl. precision. The data on these classes are very self-consistent. Very nearly the same is true of aldehydes and ketones. Major discrepancies exist in the classes of acids and esters and a few key compds. deviate seriously from other members of their class.
33. 33
  Chan, S. I.; Zinn, J.; Gwinn, W. D. Trimethylene Oxide. II. Structure, Vibration-Rotation Interaction, and Origin of Potential Function for Ring-Puckering Motion J. Chem. Phys. 1961, 34, 1319– 1329 DOI: 10.1063/1.1731739
  33
  Trimethylene oxide. II. Structure, vibration-rotation interaction, and origin of potential function for ring-puckering motion
  Chan, Sunney I.; Zinn, John; Gwinn, William D.
  Journal of Chemical Physics (1961), 34 (), 1319-29CODEN: JCPSA6; ISSN:0021-9606.
  cf. CA 55, 16149e. From the microwave spectra reported (loc. cit.), the structural parameters are calcd.; for trimethylene oxide (I), I-2,2,4,4-d4, I-O18, and I-3-d the effective moments of inertia of various vibrational states and rotational consts. are tabulated; from the latter, the parameters for the hypothetical planar I mol. are extrapolated. All bond angles and interat. distances of the ground, 1st excited, and planar states, and preferred structure are listed. The preferred parameters are: r(C-C) = 1.549 ± 0.003 A., r(C-O) = 1.449 ± 0.002 A., r(Cβ-Hβ) = 1.091 ± 0.002 A., r(Cβ-Hβ) = 1.100 ± 0.003 A., angle Cα-Cβ-Cα = 84°33' ± 1', angle Cα-O-Cα = 91°59' ± 7', angle Cβ-Cα-O = 91°44' ± 3', angle Hα-Cα-Hα = 110°18' ± 10', angle Hβ-Cβ-Hβ = 110°41' ± 3'. The α-methylene planes are slightly deflected towards the O, away from the bisectors of the angles Cβ-Cα-O. The actual angle of deflection is uncertain. By use of these parameters, models are constructed to calc. the vibration-rotation interaction due to the ring puckering vibration. The exptl. observed rotational const. variations are well reproduced if the out-of-plane bending motion is assumed to follow a curvilinear path without any stretching. The potential function detd. is interpreted in terms of force fields within the mol.
34. 34
  Luger, P.; Buschmann, J. Oxetane: The First X-Ray Analysis of a Nonsubstituted Four-Membered Ring J. Am. Chem. Soc. 1984, 106, 7118– 7121 DOI: 10.1021/ja00335a041
  34
  Oxetane: the first x-ray analysis of a nonsubstituted four-membered ring
  Luger, P.; Buschmann, J.
  Journal of the American Chemical Society (1984), 106 (23), 7118-21CODEN: JACSAT; ISSN:0002-7863.
  Crystallog. data, bond lengths and bond angles were detd. for oxetane by x-ray anal. at 90 and 140 K. The ring has exact Cs symmetry and is puckered with an angle of 10.7(1)° (90 K) and 8.7(2)° (140 K). The C-O bond length of 1.460(1) Å at 90 K is unusually large for a C-O single bond.
35. 35
  Gwinn, W. D. Information Pertaining to Molecular Structure, as Obtained from the Microwave Spectra of Molecules of the Asymmetric Rotor Type Discuss. Faraday Soc. 1955, 19, 43– 51 DOI: 10.1039/df9551900043
  There is no corresponding record for this reference.
36. 36
  Holan, G.; Kowala, C.; Wunderlich, J. A. X-Ray Determination of the Structure of a New Insecticide, 2,2-Di-(p-Ethoxyphenyl)-3,3-Dimethyloxetan J. Chem. Soc., Chem. Commun. 1973, 34– 34 DOI: 10.1039/c39730000034
  There is no corresponding record for this reference.
37. 37
  Searles, S.; Tamres, M. Hydrogen Bond Formation with Saturated Cyclic Ethers J. Am. Chem. Soc. 1951, 73, 3704– 3706 DOI: 10.1021/ja01152a041
  There is no corresponding record for this reference.
38. 38
  Brandon, M.; Tamres, O. P. M.; Searles, S., Jr. The Iodine Complexes of Some Saturated Cyclic Ethers.lS2 I. The Visible Region J. Am. Chem. Soc. 1960, 82, 2129– 2134 DOI: 10.1021/ja01494a010
  There is no corresponding record for this reference.
39. 39
  West, R.; Powell, D. L.; Lee, M. K. T.; Whatley, L. S. Hydrogen Bonding Studies. IX. The Thermodynamics of Hydrogen Bonding of Phenol to Ethers and Related Compounds J. Am. Chem. Soc. 1964, 86, 3227– 3229 DOI: 10.1021/ja01070a005
  39
  Hydrogen bonding studies. IX. The thermodynamics of hydrogen bonding of phenol to ethers and related compounds
  West, Robert; Powell, David L.; Lee, Margaret K. T.; Whatley, Linda S.
  Journal of the American Chemical Society (1964), 86 (16), 3227-9CODEN: JACSAT; ISSN:0002-7863.
  cf. CA 61, 2539c. The enthalpy and free energy of interaction of PhOH with 11 ethers, 2 sulfides, and 1 selenide have been detd. by a near-infrared spectrophotometric method. Chain branching α to the O atom increases the enthalpy of interaction, whereas aryl substitution decreases it. The cyclic ethers (CH2)3O, (CH2)4O, (CH2)5O, and 1,2-epoxyisobutane show about equal basicity toward PhOH. The dialkyl S and Se compds. are much weaker bases toward PhOH than analogous ethers. Implications of these findings are discussed.
40. 40
  Besseau, F.; Luçon, M.; Laurence, C.; Berthelot, M. Hydrogen-Bond Basicity pK_HB Scale of Aldehydes and Ketones J. Chem. Soc., Perkin Trans. 2 1998, 101– 108 DOI: 10.1039/a704427e
  40
  Hydrogen-bond basicity pKHB scale of aldehydes and ketones
  Besseau, Francois; Lucon, Maryvonne; Laurence, Christian; Berthelot, Michel
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1998), (1), 101-108CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)
  The thermodn. hydrogen-bond basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-aldehyde or ketone complexes in CCl4 at 298 K) has been detd. for aldehydes, aliph. ketones, cycloalkanones, diketones and quinones, halogenated ketones, pyrones and related compds., acetophenones, benzophenones and various other conjugated ketones. The relationship between pKHB and a spectroscopic scale of basicity is obscured by the presence of two stereoisomeric complexes. In the R1COMe series the electronic and steric effects of the alkyl R1 almost cancel out, whereas steric effects prevail in R1COR2. Among alkyl substituents the 1-adamantyl is the most electron-donating. In cycloalkanones the basicity sequence with ring size is 4 < 11 ∼ 12 ∼ 15 < 5 < 6 < 7 < 8. Quant. structure-basicity relationships have been established in the arom. 3- and 4-XC6H4COMe and the aliph. XCOMe series. Intramol. hydrogen bonding causes a basicity decrease in acetylacetone. Hydrogen bonding sites are discussed.
41. 41
  Besseau, F.; Laurence, C.; Berthelot, M. Hydrogen-Bond Basicity of Esters, Lactones and Carbonates J. Chem. Soc., Perkin Trans. 2 1994, 485– 489 DOI: 10.1039/p29940000485
  41
  Hydrogen-bond basicity of esters, lactones and carbonates
  Besseau, Francois; Laurence, Christian; Berthelot, Michel
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1994), (3), 485-9CODEN: JCPKBH; ISSN:0300-9580.
  A thermodn. hydrogen-bond-basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-base complexes in CCl4) has been detd. for esters, lactones and carbonates, and correlated to a spectroscopic basicity scale. In the esters R1CO2R2 the hydrogen-bond basicity is decreased by bulky alkyl R1 substituents (steric effect) but increased by branched and lengthened alkyl R2 substituents (electronic effects). Quant. structure-basicity relationships have been established in the XCO2Et (X varying from CF3 to Me2N) and XC6H4CO2Et (X varying from 4-NO2 to 4-Me2N) series. Vinylol. strongly increases hydrogen-bond basicity: Me2NCH:CHCO2Et is the most basic ester presently known. Cyclization increases the hydrogen-bond basicity of esters and carbonates.
42. 42
  Le Questel, J.-Y.; Laurence, C.; Lachkar, A.; Helbert, M.; Berthelot, M. Hydrogen-Bond Basicity of Secondary and Tertiary Amides, Carbamates, Ureas and Lactams J. Chem. Soc., Perkin Trans. 2 1992, 2091– 2094 DOI: 10.1039/p29920002091
  42
  Hydrogen-bond basicity of secondary and tertiary amides, carbamates, ureas and lactams
  Le Questel, Jean Yves; Laurence, Christian; Lachkar, Abdeljalil; Helbert, Maryvonne; Berthelot, Michel
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1992), (12), 2091-4CODEN: JCPKBH; ISSN:0300-9580.
  A hydrogen-bond basicity scale pKHB (logarithm of the formation const. of 4-fluorophenol-base complexes in CCl4) has been measured for the title compds. The hydrogen-bonding site is the carbonyl group, even for the very hindered amide Me3CCON(C6H11)2. In the amides R1CONR2R3 the hydrogen-bond basicity is decreased more by bulky R1 substituents on the carbonyl carbon than by bulky R2 and R3 substituents on nitrogen. The field effect of X substituents operates more effectively on hydrogen-bond basicity than the resonance effect in the XCONMe2 series. The hydrogen-bond basicity is increased by six-membered cyclization.
43. 43
  Berthelot, M.; Besseau, F.; Laurence, C. The Hydrogen-Bond Basicity pK_HB Scale of Peroxides and Ethers Eur. J. Org. Chem. 1998, 1998, 925– 931 DOI: 10.1002/(SICI)1099-0690(199805)1998:5<925::AID-EJOC925>3.0.CO;2-F
  There is no corresponding record for this reference.
44. 44
  Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. Plant Antitumor Agents. VI. The Isolation and Structure of Taxol, a Novel Antileukemic and Antitumor Agent from Taxus Brevifolia J. Am. Chem. Soc. 1971, 93, 2325– 2327 DOI: 10.1021/ja00738a045
  44
  Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia
  Wani, Mansukhlal C.; Taylor, Harold Lawrence; Wall, Monroe E.; Coggon, Philip; McPhail, Andrew T.
  Journal of the American Chemical Society (1971), 93 (9), 2325-7CODEN: JACSAT; ISSN:0002-7863.
  Taxol (I), a complex ester with a taxane ring system exhibiting potent antileukemic and antitumor properties, was isolated from Taxus brevifolia (yew). BzNHCH(Ph)CH(OH)CO2Me and 5β,16-epoxy-1β,-2α,4α,7β,10β,13α-hexahydroxytax-11-en-9-one 4α-acetate 2α-benzoate are obtained by methanolysis of I. Based on chem. evidence, I is 5β,16-epoxy-1β,2α,4α,7β,10β,13α-hexahydroxytax-11-en-9-one 4α,10β-diacetate 2α-benzoate 13α-(3-benzamido-2-hydroxy-3-phenylpropionate).
45. 45
  Gunatilaka, A. A. L.; Ramdayal, F. D.; Sarragiotto, M. H.; Kingston, D. G. I.; Sackett, D. L.; Hamel, E. Synthesis and Biological Evaluation of Novel Paclitaxel (Taxol) D-Ring Modified Analogues J. Org. Chem. 1999, 64, 2694– 2703 DOI: 10.1021/jo982095h
  There is no corresponding record for this reference.
46. 46
  Boge, T. C.; Hepperle, M.; Vander Velde, D. G.; Gunn, C. W.; Grunewald, G. L.; Georg, G. I. The Oxetane Conformational Lock of Paclitaxel: Structural Analysis of D-Secopaclitaxel Bioorg. Med. Chem. Lett. 1999, 9, 3041– 3046 DOI: 10.1016/S0960-894X(99)00521-1
  There is no corresponding record for this reference.
47. 47
  Marder-Karsenti, R.; Dubois, J.; Bricard, L.; Guénard, D.; Guéritte-Voegelein, F. Synthesis and Biological Evaluation of D-Ring-Modified Taxanes: 5(20)-Azadocetaxel Analogs J. Org. Chem. 1997, 62, 6631– 6637 DOI: 10.1021/jo9706842
  There is no corresponding record for this reference.
48. 48
  Wang, M.; Cornett, B.; Nettles, J.; Liotta, D. C.; Snyder, J. P. The Oxetane Ring in Taxol J. Org. Chem. 2000, 65, 1059– 1068 DOI: 10.1021/jo9916075
  48
  The Oxetane Ring in Taxol
  Wang, Minmin; Cornett, Ben; Nettles, Jim; Liotta, Dennis C.; Snyder, James P.
  Journal of Organic Chemistry (2000), 65 (4), 1059-1068CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Numerous structure-activity studies combining synthesis and bioassay have been performed for the anti-cancer drug taxol. The four-membered D-ring, an oxetane, is one of four structural features regarded to be essential for biol. activity. This proposition is examd. by application of a taxol-epothilone minireceptor, Ki estn. for microtubule binding and docking of taxol analogs into a model of the taxol-tubulin complex. The two characteristics considered responsible for oxetane function were examd.: (1) rigidification of the tetracyclic taxol core to provide an appropriate framework for presenting the C-2, C-4, C-13 side chains to the microtubule protein and (2) service as a hydrogen-bond acceptor. An energy decompn. anal. for a series of taxol analogs demonstrated the oxetane ring clearly operates by both mechanisms. A broader anal. of four-membered ring contg. compds., C- and D-seco derivs., and structures with no oxetane equiv. underscores that the four-membered ring is not necessary for taxol analog bioactivity. Other functional groups and ligand-protein binding characteristics are fully capable of delivering taxol biobehavior as effectively as the oxetane D-ring. This information may contribute to the design and development of novel anticancer drugs.
49. 49
  Wang, S.-R.; Yang, C.-G.; Sánchez-Murcia, P. A.; Snyder, J. P.; Yan, N.; Sáez-Calvo, G.; Díaz, J. F.; Gago, F.; Fang, W.-S. Restoration of Microtubule Interaction and Cytotoxicity in D-Seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-Allyloxy Groups Org. Lett. 2015, 17, 6098– 6101 DOI: 10.1021/acs.orglett.5b03119
  49
  Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups
  Wang, Shao-Rong; Yang, Chun-Gang; Sanchez-Murcia, Pedro A.; Snyder, James P.; Yan, Ning; Saez-Calvo, Gonzalo; Diaz, Jose Fernando; Gago, Federico; Fang, Wei-Shuo
  Organic Letters (2015), 17 (24), 6098-6101CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepd. from paclitaxel. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane (I) is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than paclitaxel on tubulin polymn. promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and mol. modeling studies. From these results, the authors draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.
50. 50
  Hefner, J.; Rubenstein, S. M.; Ketchum, R. E.; Gibson, D. M.; Williams, R. M.; Croteau, R. Cytochrome P450-Catalyzed Hydroxylation of Taxa-4(5),11(12)-diene to Taxa-4(20),11(12)-dien-5α-ol: The First Oxygenation Step in Taxol Biosynthesis Chem. Biol. 1996, 3, 479– 489 DOI: 10.1016/S1074-5521(96)90096-4
  50
  Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5α-ol: the first oxygenation step in taxol biosynthesis
  Hefner, Jerry; Rubenstein, Steven M.; Ketchum, Raymond E. B.; Gibson, Donna M.; Williams, Robert M.; Croteau, Rodney
  Chemistry & Biology (1996), 3 (6), 479-489CODEN: CBOLE2; ISSN:1074-5521. (Current Biology)
  The biosynthesis of taxol involves the cyclization of the common isoprenoid intermediate geranylgeranyl diphosphate to taxa-4(5),11(12)-diene followed by extensive, largely oxidative, modification of this diterpene olefin. We set out to define the first oxygenation step in taxol biosynthesis. Microsomal enzymes from Taxus stem and cultured cells were used to define the first hydroxylation of taxadiene. We confirmed the structure of the reaction product (taxa-4(20),11(12)-dien-5α-ol) by synthesizing this compd. The responsible biol. catalyst was characterized as a cytochrome P 450 (heme thiolate protein). In vivo studies confirmed that taxadienol is a biosynthetic intermediate and indicated that the hydroxylation step that produces this product is slow relative to subsequent metabolic transformations. The structure of the first oxygenated intermediate on the taxol pathway establishes that the hydroxylation reaction proceeds with an unusual double bond migration that limits the mechanistic possibilities for subsequent elaboration of the oxetane moiety of taxol. The reaction is catalyzed by a cytochrome P 450, suggesting that the 7 remaining oxygenation steps in taxol biosynthesis may involve similar catalysts. Because the first oxygenation step is slow relative to subsequent metabolic transformations, it may be possible to speed taxol biosynthesis by isolating and manipulating the gene for the taxadiene-5-hydroxylase that catalyzes this reaction.
51. 51
  Guéritte-Voegelein, F.; Guénard, D.; Potier, P. Taxol and Derivatives: A Biogenetic Hypothesis J. Nat. Prod. 1987, 50, 9– 18 DOI: 10.1021/np50049a002
  51
  Taxol and derivatives: a biogenetic hypothesis
  Gueritte-Voegelein, Francoise; Guenard, Daniel; Potier, Pierre
  Journal of Natural Products (1987), 50 (1), 9-18CODEN: JNPRDF; ISSN:0163-3864.
  A review with 70 refs. on structure differences of compds. isolated from Taxus species and their relation to a biogenic approach and synthesis of taxol (I).
52. 52
  Swindell, C. S.; Britcher, S. F. Construction of the Taxane C-Ring Epoxy Alcohol Moiety and Examination of its Possible Involvement in the Biogenesis of the Taxane 3-Oxetanol Structure J. Org. Chem. 1986, 51, 793– 797 DOI: 10.1021/jo00356a005
  52
  Construction of the taxane C-ring epoxy alcohol moiety and examination of its possible involvement in the biogenesis of the taxane 3-oxetanol structure
  Swindell, Charles S.; Britcher, Susan F.
  Journal of Organic Chemistry (1986), 51 (6), 793-7CODEN: JOCEAH; ISSN:0022-3263.
  A stereospecific synthesis of a model compd. I (R = H), contg. the 2,3-epoxy alc. moiety present in the C-ring of several taxane diterpenes, was accomplished. Thus, epoxide II was converted to allylic alc. III, which upon epoxidn. gave epoxide IV, followed by treatment with hydroxide to give I (R = H). Methanesulfonate I (R = MeSO2) gave ketone V upon solvolysis in aq. MeCN. Two possible mechanisms for this transformation are provided. This last expt. was designed to evaluate a described suggestion regarding the biogenesis of the taxane C-ring 3-oxetanol moiety.
53. 53
  Willenbring, D.; Tantillo, D. J. Mechanistic Possibilities for Oxetane Formation in the Biosynthesis of Taxol’s D Ring Russ. J. Gen. Chem. 2008, 78, 723– 731 DOI: 10.1134/S1070363208040336
  53
  Mechanistic possibilities for oxetane formation in the biosynthesis of Taxol's D ring
  Willenbring, Dan; Tantillo, Dean J.
  Russian Journal of General Chemistry (2008), 78 (4), 723-731CODEN: RJGCEK; ISSN:1070-3632. (Pleiades Publishing, Ltd.)
  Three mechanistic possibilities for the formation of the oxetane (D ring) of Taxol were examd. at various levels of theory [B3LYP/6-31+G(d,p), mPW1PW91/6-31+G(d,p), and MP2/6-31+G(d,p)] including one mechanism involving an unusual oxabicyclobutonium ion intermediate. The mechanisms examd. differ considerably in terms of their predicted inherent activation barriers, and the requirements for acceleration of each by an enzyme active site are outlined. Our calcns. provide an important starting point for future studies in this area. Also examd. were previously published calcns. on simple oxabicyclobutonium ions, as well as the all-carbon analog of the pathway involving the oxabicyclobutonium ion.
54. 54
  Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii, A.; Takita, T. Oxetanocin, a Novel Nucleoside from Bacteria J. Antibiot. 1986, 39, 1623– 1625 DOI: 10.7164/antibiotics.39.1623
  54
  Oxetanocin, a novel nucleoside from bacteria
  Shimada, Nobuyoshi; Hasegawa, Shigeru; Harada, Takashi; Tomisawa, Takayuki; Fujii, Akio; Takita, Tomohisa
  Journal of Antibiotics (1986), 39 (11), 1623-5CODEN: JANTAJ; ISSN:0021-8820.
  The prodn., isolation, and chem. and biol. properties of oxetanocin (9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanyl]adenine) from Bacillus megaterium are reported. Oxetanocin at the levels tested showed activity against herpes simplex virus-II and cytotoxicity against Vero cells, but no activity against vesicular stomatitis virus. It inhibited growth of HeLa cells in vitro and showed strong antibacterial activity against Staphylococcus aureus and several Bacillus species. Adenine and adenosine were antagonistic toward the antibacterial activity of oxetanocin; guanosine and the inosine showed a weak antagonistic effect. I.v. infection of oxetanocin to mice showed no toxicity.
55. 55
  Omura, S.; Murata, M.; Imamura, N.; Iwai, Y.; Tanaka, H.; Furusaki, A.; Matsumoto, H. Oxetin, a New Antimetabolite from an Actinomycete. Fermentation, Isolation, Structure and Biological Activity J. Antibiot. 1984, 37, 1324– 1332 DOI: 10.7164/antibiotics.37.1324
  55
  Oxetin, a new antimetabolite from an actinomycete. Fermentation, isolation, structure and biological activity
  Omura, Satoshi; Murata, Masatsune; Imamura, Nobutaka; Iwai, Yuzuru; Tanaka, Haruo; Furusaki, Akio; Matsumoto, Takeshi
  Journal of Antibiotics (1984), 37 (11), 1324-32CODEN: JANTAJ; ISSN:0021-8820.
  A new amino acid-antimetabolite, oxetin (I), was isolated from a fermn. broth of a Streptomyces sp. OM-2317, a soil isolate. The chem. structure was elucidated as (2R,3S)-3-amino-2-oxetane carboxylic acid by anal. of the spectral data and by x-ray diffraction methods. I is the first natural product possessing an oxetane ring. Certain microorganisms were inhibited by I only when cultivated in minimal media. The inhibitory action was reversed by several amino acids such as L-isoleucine, L-methionine, L-valine, and L-glutamine. It also exhibited herbicidal activity and inhibited glutamine synthetase from spinach leaves.
56. 56
  Han, Q.; Zhang, J.; Lu, Y.; Wu, Y.; Zheng, Q.; Sun, H. A Novel Cytotoxic Oxetane ent-Kauranoid from Isodon Japonicus Planta Med. 2004, 70, 581– 584 DOI: 10.1055/s-2004-827165
  56
  A novel cytotoxic oxetane ent-kauranoid from Isodon japonicus
  Han, Quanbin; Zhang, Jixia; Lu, Yang; Wu, Yunshan; Zheng, Qitai; Sun, Handong
  Planta Medica (2004), 70 (6), 581-584CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
  A novel 11,20:1,20-diepoxy-ent-kaurane diterpenoid, maoyecrystal I (I), was isolated from Isodon japonicus, and its structure was elucidated by spectroscopic methods and comparison with another new ent-kauranoid, rubescensin W (II) from Isodon rubescens var. taihangensis. The structure of II was detd. by single crystal x-ray diffraction anal. A bioassay of their cytotoxicity against K562 cells showed that the oxetane group of I might be a bioactive moiety.
57. 57
  Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Burgess, J. P.; Riswan, S.; Setyowati, F. M.; Saribi, A. M.; Soejarto, D. D. A Hexacyclic ent-Trachylobane Diterpenoid Possessing an Oxetane Ring from Mitrephora Glabra Org. Lett. 2005, 7, 5709– 5712 DOI: 10.1021/ol052498l
  57
  A Hexacyclic ent-Trachylobane Diterpenoid Possessing an Oxetane Ring from Mitrephora glabra
  Li, Chen; Lee, Dongho; Graf, Tyler N.; Phifer, Sharnelle S.; Nakanishi, Yuka; Burgess, Jason P.; Riswan, Soedarsono; Setyowati, Fransisca M.; Saribi, Achmad M.; Soejarto, Djaja D.; Farnsworth, Norman R.; Falkinham, Joseph O., III; Kroll, David J.; Kinghorn, A. Douglas; Wani, Mansukh C.; Oberlies, Nicholas H.
  Organic Letters (2005), 7 (25), 5709-5712CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  Three new ent-trachylobane diterpenoids (I-III) were isolated and structures elucidated from Mitrephora glabra Scheff. (Annonaceae). Mitrephorone A possesses a hexacyclic ring system with adjacent ketone moieties and an oxetane ring, both of which are unprecedented among trachylobanes. All compds. were evaluated for cytotoxicity against a panel of cancer cells, where 1 displayed the most potent and broadest activity, and against a battery of antimicrobial assays, where all compds. were approx. equipotent.
58. 58
  Hamberg, M.; Svensson, J.; Samuelsson, B. Thromboxanes: A New Group of Biologically Active Compounds Derived from Prostaglandin Endoperoxides Proc. Natl. Acad. Sci. U. S. A. 1975, 72, 2994– 2998 DOI: 10.1073/pnas.72.8.2994
  58
  Thromboxanes. New group of biologically active compounds derived from prostaglandin endoperoxides
  Hamberg, Mats; Svensson, Jan; Samuelsson, Bengt
  Proceedings of the National Academy of Sciences of the United States of America (1975), 72 (8), 2994-8CODEN: PNASA6; ISSN:0027-8424.
  An unstable (t1/2 at 37° = 32 sec) intermediate, thromboxane A2, was detected in the conversion of prostaglandin G2 into thromboxane B2 in platelets. The intermediate was trapped by addn. of MeOH, EtOH, or NaN3 to suspensions of washed human platelets incubated for 30 sec with arachidonic acid or prostaglandin G2. The structures of the resulting derivs. demonstrated that the intermediate possessed an oxane ring as in thromboxane B2 but lacked its hemiacetal OH group. Addnl. expts. using 18O or arachidonic acid 2H8 in the formation of thromboxane B2 and CH3O2H for the trapping of thromboxane A2, together with information on the t1/2 of the intermediate, indicated the presence of an oxetane structure in thromboxane A2. Incubation of arachidonic acid or prostaglandin G2 with washed platelets led to the formation of an unstable factor that induced irreversible platelet aggregation and caused release of serotonin-14C from platelets that were incubated with labeled serotonin. The properties and the mode of formation of this factor indicated that it was identical with thromboxane A2. Furthermore, evidence was presented that the more unstable and major component of rabbit aorta contracting substance formed in platelets and guinea pig lung is also thromboxane A2.
59. 59
  Huang, J.; Yokoyama, R.; Yang, C.; Fukuyama, Y. Merrilactone A, a Novel Neurotrophic Sesquiterpene Dilactone from Illicium Merrillianum Tetrahedron Lett. 2000, 41, 6111– 6114 DOI: 10.1016/S0040-4039(00)01023-6
  59
  Merrilactone A, a novel neurotrophic sesquiterpene dilactone from Illicium merrillianum
  Huang, J.-m.; Yokoyama, R.; Yang, C.-s.; Fukuyama, Y.
  Tetrahedron Letters (2000), 41 (32), 6111-6114CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
  Merrilactone A (I), isolated from the pericarps of Illicium merrillianum, shows an intriguing neurotrophic activity in the cultures of fetal rat cortical neurons. Its structure has been elucidated to be a unique sesquiterpene bearing two γ-lactones and an oxetane ring by extensive analyses of spectral data and then confirmed by X-ray crystallog. anal. Further, the abs. configuration has been established by the modified Mosher's method.
60. 60
  Pullaiah, K. C.; Surapaneni, R. K.; Rao, C. B.; Albizati, K. F.; Sullivan, B. W.; Faulkner, D. J.; He, C. H.; Clardy, J. Dictyoxetane, a Novel Diterpene from the Brown Alga Dictyota Dichotoma from the Indian Ocean J. Org. Chem. 1985, 50, 3665– 3666 DOI: 10.1021/jo00219a057
  60
  Dictyoxetane, a novel diterpene from the brown alga Dictyota dichotoma from the Indian Ocean
  Pullaiah, K. C.; Surapaneni, R. K.; Rao, C. Bheemasankara; Albizati, Kim F.; Sullivan, Brian W.; Faulkner, D. John; He, Cun Heng; Clardy, Jon
  Journal of Organic Chemistry (1985), 50 (19), 3665-6CODEN: JOCEAH; ISSN:0022-3263.
  Dictyoxetane (I), isolated from an Indian Ocean specimen of the brown alga D. dichotoma, is the 1st example of a new tricyclic diterpene C skeleton. The structure of I was detd. by x-ray anal.
61. 61
  Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. Synthesis of a 2,7-Dioxatricyclo[4.2.1.0 3,8 ]nonane: A Model Study for Possible Application in a Synthesis of Dictyoxetane J. Org. Chem. 1996, 61, 9135– 9145 DOI: 10.1021/jo961680k
  There is no corresponding record for this reference.
62. 62
  Loh, J.; Carlson, R. W.; York, W. S.; Stacey, G. Bradyoxetin, a Unique Chemical Signal Involved in Symbiotic Gene Regulation Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14446– 14451 DOI: 10.1073/pnas.222336799
  There is no corresponding record for this reference.
63. 63
  Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Oxetanes as Promising Modules in Drug Discovery Angew. Chem., Int. Ed. 2006, 45, 7736– 7739 DOI: 10.1002/anie.200602343
  63
  Oxetanes as promising modules in drug discovery
  Wuitschik, Georg; Rogers-Evans, Mark; Mueller, Klaus; Fischer, Holger; Wagner, Bjoern; Schuler, Frnaz; Polonnchuk, Liudmila; Carreira, Erick M.
  Angewandte Chemie, International Edition (2006), 45 (46), 7736-7739CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Introduction of an oxetane ring results in remarkably improved physico- and biochem. properties of the underlying scaffold. The oxetane ring confers enhanced soly., reduces the metabolic degrdn., lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
64. 64
  Wuitschik, G.Oxetanes in Drug Discovery; Ph.D. Thesis, ETH Zurich, 2008.
  There is no corresponding record for this reference.
65. 65
  Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. Oxetanes in Drug Discovery: Structural and Synthetic Insights J. Med. Chem. 2010, 53, 3227– 3246 DOI: 10.1021/jm9018788
  65
  Oxetanes in Drug Discovery: Structural and Synthetic Insights
  Wuitschik, Georg; Carreira, Erick M.; Wagner, Bjorn; Fischer, Holger; Parrilla, Isabelle; Schuler, Franz; Rogers-Evans, Mark; Muller, Klaus
  Journal of Medicinal Chemistry (2010), 53 (8), 3227-3246CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The use of oxetanes as replacements for gem-di-Me or carbonyl groups and their effects on the aq. soly., lipophilicity, metabolic stability, and conformation for various compds. are studied; methods for the prepn. of a variety of substituted oxetanes are given. The magnitude of changes in properties and in metabolic stability with oxetane substitution depends on the structural context; for example, substitution of a gem-di-Me group with an oxetane, aq. soly. may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degrdn. in most cases. Incorporation of an oxetane into an aliph. chain increases in some cases the preference for synclinal conformations rather than antiplanar conformations of the chain. Spirocyclic oxetanes such as an oxazaspiroheptane resemble commonly used fragments in drug discovery, such as morpholines, and in some cases increase aq. soly. more effectively than morpholines. An improved chemoselective oxidn. of 3-oxetanol to 3-oxetanone is disclosed; olefination of 3-oxetanone by a variety of methods yields alkylideneoxetanes I [R = (EtO)2P(:O), OHC, O2N, EtO2C, NC, PhO2S, MeCO, 1-(4-chlorophenyl)-1-cyclobutanecarbonyl]. I (R = EtO2C, OHC, O2N) undergo addn. reactions with nucleophiles such as amines, carbonyl compds., and arylboronic acids to give oxetanes such as II. The crystal structures of a variety of oxetanes are detd.
66. 66
  Waring, M. J. Lipophilicity in Drug Discovery Expert Opin. Drug Discovery 2010, 5, 235– 248 DOI: 10.1517/17460441003605098
  66
  Lipophilicity in drug discovery
  Waring, Michael J.
  Expert Opinion on Drug Discovery (2010), 5 (3), 235-248CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)
  A review. Importance of the field: The role of lipophilicity in detg. the overall quality of candidate drug mols. is of paramount importance. Recent developments suggest that, as well as detg. pre-clin. ADMET (absorption, distribution, metab., elimination and toxicol.) properties, compds. of optimal lipophilicity might have increased chances of success in development. Areas covered in this review: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compd. Quality' with lipophilicity. What the reader will gain: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region. Take home message: The review of the data shows that this optimal space is defined by a narrow range of logD between ∼ 1 and 3. Some of the implications of this for medicinal chem. optimization are discussed.
67. 67
  Moore, J. C.; Battino, R.; Rettich, T. R.; Handa, Y. P.; Wilhelm, E. Partial Molar Volumes of “Gases” at Infinite Dilution in Water at 298.15 K J. Chem. Eng. Data 1982, 27, 22– 24 DOI: 10.1021/je00027a005
  There is no corresponding record for this reference.
68. 68
  Edward, J. T.; Farrell, P. G.; Shahidi, F. Partial Molar Volumes of Organic Compounds in Water. Part 1. – Ethers, Ketones, Esters and Alcohols J. Chem. Soc., Faraday Trans. 1 1977, 73, 705– 714 DOI: 10.1039/f19777300705
  68
  Partial molar volumes of organic compounds in water. Part 1. Ethers, ketones, esters, and alcohols
  Edward, John T.; Farrell, Patrick G.; Shahidi, Fereidoon
  Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases (1977), 73 (5), 705-14CODEN: JCFTAR; ISSN:0300-9599.
  The partial molar vols. of 81 ethers, ketones, esters, and alcs. in H2O at 25.0° were detd. and related to their van der Waals vols. by 2 equations, for spherical and cylindrical mols., resp. Allowance was made for the void vol. assocd. with each mol. Because of H bonding to H2O, the calcd. vols. must be reduced by a const. amt. for each CO or OH group present, but not for the O atoms of the ethers. For diols, the void vol. per addnl. CH2 group remains const. for straight-chain mols. (i.e., cylinders) but decreases with the no. of C atoms for spherical mols., as is predicted.
69. 69
  Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F. Spirocyclic Oxetanes: Synthesis and Properties Angew. Chem., Int. Ed. 2008, 47, 4512– 4515 DOI: 10.1002/anie.200800450
  69
  Spirocyclic oxetanes: synthesis and properties
  Wuitschik, Georg; Rogers-Evans, Mark; Buckl, Andreas; Bernasconi, Maurizio; Marki, Moritz; Godel, Thierry; Fischer, Holger; Wagner, Bjorn; Parrilla, Isabelle; Schuler, Franz; Schneider, Josef; Alker, Andre; Schweizer, W. Bernd; Muller, Klaus; Carreira, Erick M.
  Angewandte Chemie, International Edition (2008), 47 (24), 4512-4515CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Spirocyclic oxetanes are described as analogs of morpholine and also as topol. siblings of their carbonyl counterparts. They are particularly promising in terms of both their physicochem. properties and the ease with which they can be grafted onto mol. structures. The data collected highlight oxetanes as both the hydrophilic sister of a gem-di-Me unit and the carbonyl group's lipophilic brother.
70. 70
  Fujishima, T.; Nozaki, T.; Suenaga, T. Design and Synthesis of Novel 1,25-Dihydroxyvitamin D3 Analogues Having a Spiro-Oxetane Fused at the C2 Position in the A-Ring Bioorg. Med. Chem. 2013, 21, 5209– 5217 DOI: 10.1016/j.bmc.2013.06.032
  There is no corresponding record for this reference.
71. 71
  Fujishima, T.; Suenaga, T.; Nozaki, T. Concise Synthesis and Characterization of Novel Seco-Steroids Bearing a Spiro-Oxetane instead of a Metabolically Labile C3-Hydroxy Group Tetrahedron Lett. 2014, 55, 3805– 3808 DOI: 10.1016/j.tetlet.2014.05.060
  There is no corresponding record for this reference.
72. 72
  Burkhard, J.; Carreira, E. M. 2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions Org. Lett. 2008, 10, 3525– 3526 DOI: 10.1021/ol801293f
  72
  2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions
  Burkhard, Johannes; Carreira, Erick M.
  Organic Letters (2008), 10 (16), 3525-3526CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc-N'-aryl-2,6-diazaspiro[3.3]heptanes.
73. 73
  Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Müller, K.; Carreira, E. M. Synthesis of Azaspirocycles and Their Evaluation in Drug Discovery Angew. Chem., Int. Ed. 2010, 49, 3524– 3527 DOI: 10.1002/anie.200907108
  73
  Synthesis of Azaspirocycles and their Evaluation in Drug Discovery
  Burkhard, Johannes A.; Wagner, Bjoern; Fischer, Holger; Schuler, Franz; Mueller, Klaus; Carreira, Erick M.
  Angewandte Chemie, International Edition (2010), 49 (20), 3524-3527, S3524/1-S3524/60CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Readily synthesized heteroatom-substituted spiro[3.3]heptanes generally show higher aq. soly. than their cyclohexane analogs, and show a trend towards higher metabolic stability. The novel framework can be mounted onto scaffolds of druglike structures, such as fluoroquinolones, to afford active compds. with similar or even improved metabolic stability.
74. 74
  Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks Org. Lett. 2012, 14, 66– 69 DOI: 10.1021/ol2028459
  74
  Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks
  Burkhard, Johannes A.; Guerot, Carine; Knust, Henner; Carreira, Erick M.
  Organic Letters (2012), 14 (1), 66-69CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The prepn. of versatile azaspiro[3.3]heptanes, e.g., I, carrying multiple exit vectors, is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.
75. 75
  Burkhard, J. A.; Guérot, C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Synthesis and Structural Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks for Medicinal Chemistry Org. Lett. 2010, 12, 1944– 1947 DOI: 10.1021/ol1003302
  75
  Synthesis and Structural Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks for Medicinal Chemistry
  Burkhard, Johannes A.; Guerot, Carine; Knust, Henner; Rogers-Evans, Mark; Carreira, Erick M.
  Organic Letters (2010), 12 (9), 1944-1947CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes, such as 1,6-diazaspiro[3.3]heptanes, is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallog. structures.
76. 76
  Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery Org. Lett. 2011, 13, 6134– 6136 DOI: 10.1021/ol2025313
  76
  Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery
  Li, Dong-Bo; Rogers-Evans, Mark; Carreira, Erick M.
  Organic Letters (2011), 13 (22), 6134-6136CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Step-economic and scalable syntheses of novel thiaazaspiro[3.4]octanes I (X = S, SO2, Y = CH2; X = CH2, Y = S, SO2; Z = CO, CHOH, CHNH2, CHCO2H, etc.) are reported. These spirocycles and some related intermediates can serve as uncharted multifunctional modules for drug discovery chem.
77. 77
  Guérot, C.; Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Synthesis of Novel Angular Spirocyclic Azetidines Org. Lett. 2011, 13, 780– 783 DOI: 10.1021/ol103050c
  77
  Synthesis of Novel Angular Spirocyclic Azetidines
  Guerot, Carine; Tchitchanov, Boris H.; Knust, Henner; Carreira, Erick M.
  Organic Letters (2011), 13 (4), 780-783CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The syntheses of a variety of novel angular azaspiro[3.3]heptanes, e.g., I, are reported. Gem-Difluoro and gem-di-Me variants of the angular 1,6-diazaspiro[3.3]heptane module were prepd. in high yields using efficient sequences. Addnl., a practical one-pot synthesis of 5-oxo-2-azaspiro[3.3]heptanes and subsequent conversions into functionalized derivs. are described. The methods reported are amenable to the synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale.
78. 78
  Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes Org. Lett. 2013, 15, 4766– 4769 DOI: 10.1021/ol402127b
  78
  Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes
  Li, Dong Bo; Rogers-Evans, Mark; Carreira, Erick M.
  Organic Letters (2013), 15 (18), 4766-4769CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  New classes of thia/oxa-azaspiro[3.4]octanes are synthesized through the implementation of robust and step-economic routes. The targeted spirocycles have been designed to act as novel, multifunctional, and structurally diverse modules for drug discovery. Furthermore, enantioselective approaches to the spirocycles are reported.
79. 79
  Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly, M. G. Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl–Aryl Suzuki Coupling Org. Lett. 2008, 10, 3259– 3262 DOI: 10.1021/ol8011327
  79
  Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl-Aryl Suzuki Coupling
  Duncton, Matthew A. J.; Estiarte, M. Angels; Tan, Darlene; Kaub, Carl; O'Mahony, Donogh J. R.; Johnson, Russell J.; Cox, Matthew; Edwards, William T.; Wan, Min; Kincaid, John; Kelly, Michael G.
  Organic Letters (2008), 10 (15), 3259-3262CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chem. An efficient approach to installing these two modules into arom. systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.
80. 80
  Burkhard, J. A.; Wuitschik, G.; Plancher, J.-M.; Rogers-Evans, M.; Carreira, E. M. Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide Org. Lett. 2013, 15, 4312– 4315 DOI: 10.1021/ol401705a
  80
  Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide
  Burkhard, Johannes A.; Wuitschik, Georg; Plancher, Jean-Marc; Rogers-Evans, Mark; Carreira, Erick M.
  Organic Letters (2013), 15 (17), 4312-4315CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Oxetanes are used in drug discovery to enable physicochem. and metabolic property enhancement for the structures to which they are grafted. An imide C=O to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochem. and in vitro properties of the parent drugs, with an important exception: oxetane analog I displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metab., blocking in vivo racemization, and potentially altering teratogenicity is appealing.
81. 81
  Dowling, J. E.; Alimzhanov, M.; Bao, L.; Block, M. H.; Chuaqui, C.; Cooke, E. L.; Denz, C. R.; Hird, A.; Huang, S.; Larsen, N. A. Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo ACS Med. Chem. Lett. 2013, 4, 800– 805 DOI: 10.1021/ml400197u
  81
  Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo
  Dowling, James E.; Alimzhanov, Marat; Bao, Larry; Block, Michael H.; Chuaqui, Claudio; Cooke, Emma L.; Denz, Christopher R.; Hird, Alex; Huang, Shan; Larsen, Nicholas A.; Peng, Bo; Pontz, Timothy W.; Rivard-Costa, Caroline; Saeh, Jamal Carlos; Thakur, Kumar; Ye, Qing; Zhang, Tao; Lyne, Paul D.
  ACS Medicinal Chemistry Letters (2013), 4 (8), 800-805CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors, e.g., I, of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched mol. pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKTS129, a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
82. 82
  Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.; Won, A.; Subramanyam, C.; Efremov, I. V.; O’Donnell, C. J. Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors J. Med. Chem. 2011, 54, 7772– 7783 DOI: 10.1021/jm200893p
  82
  Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors
  Stepan, Antonia F.; Karki, Kapil; McDonald, W. Scott; Dorff, Peter H.; Dutra, Jason K.; DiRico, Kenneth J.; Won, Annie; Subramanyam, Chakrapani; Efremov, Ivan V.; O'Donnell, Christopher J.; Nolan, Charles E.; Becker, Stacey L.; Pustilnik, Leslie R.; Sneed, Blossom; Sun, Hao; Lu, Yasong; Robshaw, Ashley E.; Riddell, David; O'Sullivan, Theresa J.; Sibley, Evelyn; Capetta, Steven; Atchison, Kevin; Hallgren, Andrew J.; Miller, Emily; Wood, Anthony; Obach, R. Scott
  Journal of Medicinal Chemistry (2011), 54 (22), 7772-7783CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A metab.-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analog 6 suffered from extensive oxidn. on the cycloalkyl motif by cytochrome P 450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and THF analogs, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further redn. in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metab., relative to its 2-substituted isomer. The slower rates of metab. with 3-substituted cyclic ethers most likely originate from redns. in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacol. studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in drug likeness of mols. through the use of the oxetane motif.
83. 83
  Stepan, A. F.; Kauffman, G. W.; Keefer, C. E.; Verhoest, P. R.; Edwards, M. Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter “Lipophilic Metabolism Efficiency” (LipMetE) and a Matched Molecular Pairs Analysis J. Med. Chem. 2013, 56, 6985– 6990 DOI: 10.1021/jm4008642
  83
  Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter "Lipophilic Metabolism Efficiency" (LipMetE) and a Matched Molecular Pairs Analysis
  Stepan, Antonia F.; Kauffman, Gregory W.; Keefer, Christopher E.; Verhoest, Patrick R.; Edwards, Martin
  Journal of Medicinal Chemistry (2013), 56 (17), 6985-6990CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We have obsd. previously that modification of ring size and substitution pattern may be used as a strategy to mitigate the metabolic instability of cycloalkyl ethers. In this article, we introduce a medicinal chem. design parameter named "lipophilic metab. efficiency" (LipMetE) that indicates that these changes in metabolic stability can be largely ascribed to changes in lipophilicity. Our matched mol. pair anal. also indicates that this finding is a general phenomenon, widely obsd. across different chemotypes. It is our hope that both the LipMetE design parameter and the results from our pairwise anal. will be useful tools for medicinal chemists.
84. 84
  Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-Guided Drug Design MedChemComm 2013, 4, 631– 652 DOI: 10.1039/c2md20317k
  84
  Metabolism-guided drug design
  Stepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.
  MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
85. 85
  Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A. Studies on the Synthesis, Stability and Conformation of 2-Sulfonyl-Oxetane Fragments Org. Biomol. Chem. 2015, 13, 5265– 5272 DOI: 10.1039/C5OB00549C
  85
  Studies on the synthesis, stability and conformation of 2-sulfonyl-oxetane fragments
  Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A.
  Organic & Biomolecular Chemistry (2015), 13 (18), 5265-5272CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  2-(Arylsulfonyl)oxetanes, I [R is H, Me-4, Cl-4, Me-2, Cl-2, Cl-3, F-4, Br-4, CF3-4, OMe-4] and II, have been prepd. as new structural motifs of interest for medicinal chem. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compds. The oxetane ring is constructed through an efficient C-C bond forming cyclization which allows the incorporation of a wide range of aryl-sulfonyl groups. Furthermore, biaryl-contg. compds. can be accessed through Suzuki-Miyaura coupling from halogenated derivs. With a no. of oxetane contg. fragment compds. available, their pH stability was assessed, indicating good half-life values for mono-substituted aryl sulfonyl oxetanes across the pH range (1 to 10). Soly. and metabolic stability data is also reported. Finally, the conformation of the fragments is assessed computationally, providing an indication of possible binding orientations.
86. 86
  Lucas, S. D.; Iding, H.; Alker, A.; Wessel, H. P.; Rauter, A. P. Oxetane δ-Amino Acids: Chemoenzymatic Synthesis of 2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic Acid J. Carbohydr. Chem. 2006, 25, 187– 196 DOI: 10.1080/07328300600732485
  86
  Oxetane δ-amino acids: chemoenzymatic synthesis of 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid
  Lucas, Susana Dias; Iding, Hans; Alker, Andre; Wessel, Hans Peter; Rauter, Amelia Pilar
  Journal of Carbohydrate Chemistry (2006), 25 (2-3), 187-196CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
  Starting from 1,2-O-isopropylidene-D-xylose, Me 2,4-anhydro-3,5-di-O-benzyl-D-lyxonate (4) was synthesized. Debenzylation and transformation of the primary hydroxyl group yielded Me 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonate (9). While transesterification of 4 under basic reaction conditions was straightforward, an analogous reaction with 9 was not successful. After screening of several lipases, the enzymic transesterification of 9 was achieved with lipase L2 from Candida antarctica to furnish the title compd. 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid in excellent yield. The stereochem. at the oxetane ring was proven by an x-ray structure of the intermediate Me 2,4-anhydro-5-azido-D-lyxonate.
87. 87
  Lucas, S. D.; Rauter, A. P.; Wessel, H. P. Synthesis of 3-Methoxyoxetane δ-Amino Acids with D-Lyxo, D-Ribo, and D-Arabino Configurations J. Carbohydr. Chem. 2008, 27, 172– 187 DOI: 10.1080/07328300802061717
  87
  Synthesis of 3-methoxyoxetane δ-amino acids with D-lyxo, D-ribo, and D-arabino configurations
  Lucas, Susana Dias; Rauter, Amelia Pilar; Wessel, Hans Peter
  Journal of Carbohydrate Chemistry (2008), 27 (3), 172-187CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
  Starting from 1,2-isopropylidene-D-xylose (I), 3-methoxyoxetane δ-amino acids with D-lyxo, D-ribo, and D-arabino configurations were synthesized. The early introduction of an azide function at C-5 of I shortened the synthetic pathway. Ring contraction of the intermediate D-xylono-1,4-lactone via triflation and treatment with base led to the corresponding 3-methoxyoxetane δ-amino ester with D-lyxo configuration (II). The analogous procedure for D-ribono-1,4-lactone furnished a mixt. of D-ribo and D-arabino esters (III) and (IV). Hydrolysis of the Me esters II, III, and IV to their corresponding δ-amino acids was successful with LiOH in THF, in contrast to that of their 3-hydroxy analog analog.
88. 88
  Lucas, S. D.; Rauter, A. P.; Schneider, J.; Wessel, H. P. Synthesis of 3-Fluoro-Oxetane δ-Amino Acids J. Carbohydr. Chem. 2009, 28, 431– 446 DOI: 10.1080/07328300903261562
  88
  Synthesis of 3-fluoro-oxetane δ-amino acids
  Lucas, Susana Dias; Rauter, Amelia Pilar; Schneider, Josef; Wessel, Hans Peter
  Journal of Carbohydrate Chemistry (2009), 28 (7 & 8), 431-446CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
  Starting from D-xylose, 2,4-anhydro-5-N-(tert-butoxycarbonyl)amino-5-deoxy-3-fluoro-D-arabinonic acid (I) (R1 = OMe; Boc = tert-butoxycarbonyl) was synthesized over 10 steps including ring contraction, fluorination, and ester hydrolysis. Bromine oxidn. of D-xylose followed by benzylidenation in a one-pot procedure led to a ca. 1:1 mixt. of lactone (II) and 2,4;3,5-dibenzylidene xylonic acid as byproduct. For the synthesis of the D-xylo deriv. (III) (R2 = OH), the chosen starting material was 1,2-O-isopropylidene-α-D-xylofuranose. A total of 14 steps including epimerization, ring contraction, fluorination, and sapon. led to the desired fluoro-oxetane δ-amino acid III (R2 = OH). Hydrolysis of the 3-fluoro-oxetane δ-amino esters I (R1 = OH) and III (R2 = OMe) by means of LiOH was successful in agreement with the results previously reported for similar 3-methoxy oxetanes, whereas chem. hydrolysis was not possible for 3-hydroxy derivs.
89. 89
  Lucas, S. D.; Fischer, H.; Alker, A.; Rauter, A. P.; Wessel, H. P. Libraries on Oxetane δ-Amino Acid Scaffolds: Syntheses and Evaluation of Physicochemical and Metabolic Properties J. Carbohydr. Chem. 2011, 30, 498– 548 DOI: 10.1080/07328303.2011.609627
  89
  Libraries on Oxetane δ-Amino Acid Scaffolds: Syntheses and Evaluation of Physicochemical and Metabolic Properties
  Lucas, Susana Dias; Fischer, Holger; Alker, Andre; Rauter, Amelia P.; Wessel, Hans Peter
  Journal of Carbohydrate Chemistry (2011), 30 (7-9), 498-548CODEN: JCACDM; ISSN:0732-8303. (Taylor & Francis, Inc.)
  Oxetane δ-amino acids were investigated as scaffolds to generate oxetane-based libraries. As pharmacophores, oxadiazoles and triazoles were built up on the scaffolds. Important physicochem. properties of target compds. were predicted in silico, and some physicochem. (soly., logD, pKa values, permeation through artificial membranes) and metabolic (intrinsic clearance) properties were detd. exptl. The compds. synthesized exhibited the desired ADMETox properties. From an in silico point of view, this work adds valuable information for the refinement of prediction tools.
90. 90
  Skoda, E. M.; Sacher, J. R.; Kazancioglu, M. Z.; Saha, J.; Wipf, P. An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility ACS Med. Chem. Lett. 2014, 5, 900– 904 DOI: 10.1021/ml5001504
  90
  An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility
  Skoda, Erin M.; Sacher, Joshua R.; Kazancioglu, Mustafa Z.; Saha, Jaideep; Wipf, Peter
  ACS Medicinal Chemistry Letters (2014), 5 (8), 900-904CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Low aq. soly. is a common challenge in drug discovery and development and can lead to inconclusive biol. assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves soly., but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly sol. drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aq. soly. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compd.
91. 91
  Sprachman, M. M.; Wipf, P. A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules Assay Drug Dev. Technol. 2012, 10, 269– 277 DOI: 10.1089/adt.2011.0421
  91
  A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules
  Sprachman, Melissa M.; Wipf, Peter
  Assay and Drug Development Technologies (2012), 10 (3), 269-277CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)
  An oxetane-substituted sulfoxide has demonstrated potential as a dimethylsulfoxide substitute for enhancing the dissoln. of org. compds. with poor aq. solubilities. This sulfoxide may find utility in applications of library storage and biol. assays. For the model compds. studied, significant soly. enhancements were obsd. using the sulfoxide as a cosolvent in aq. media. Brine shrimp, breast cancer (MDA-MB-231), and liver cell line (HepG2) toxicity data for the new additive are also presented, in addn. to comparative IC50 values for a series of PKD1 inhibitors.
92. 92
  Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design J. Med. Chem. 2011, 54, 2529– 2591 DOI: 10.1021/jm1013693
  92
  Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design
  Meanwell, Nicholas A.
  Journal of Medicinal Chemistry (2011), 54 (8), 2529-2591CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering phys. properties, reducing or redirecting metab., eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compd. optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examd. are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chem. setting has been adopted by this community.
93. 93
  St. Jean, D. J., Jr.; Fotsch, C. Mitigating Heterocycle Metabolism in Drug Discovery J. Med. Chem. 2012, 55, 6002– 6020 DOI: 10.1021/jm300343m
  93
  Mitigating Heterocycle Metabolism in Drug Discovery
  St. Jean, David J.; Fotsch, Christopher
  Journal of Medicinal Chemistry (2012), 55 (13), 6002-6020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Extensive data from metab. studies have allowed medicinal chemists to develop general principles for reducing compd. metab. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochem. of their compds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compds. If the specific site of metab. is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. While several authors have reviewed these techniques for reducing metab., there is no review that summarizes different approaches to improving them metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compds.
94. 94
  Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically Stable tert-Butyl Replacement ACS Med. Chem. Lett. 2013, 4, 514– 516 DOI: 10.1021/ml400045j
  94
  Metabolically Stable tert-Butyl Replacement
  Barnes-Seeman, David; Jain, Monish; Bell, Leslie; Ferreira, Suzie; Cohen, Scott; Chen, Xiao-Hui; Amin, Jakal; Snodgrass, Brad; Hatsis, Panos
  ACS Medicinal Chemistry Letters (2013), 4 (6), 514-516CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Susceptibility to metab. is a common issue with the tert-Bu group on compds. of medicinal interest. The authors demonstrate an approach of removing all the fully Sp3 C-Hs from a tert-Bu group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-contg. analogs had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-contg. counterparts.
95. 95
  Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success J. Med. Chem. 2009, 52, 6752– 6756 DOI: 10.1021/jm901241e
  95
  Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
  Lovering, Frank; Bikker, Jack; Humblet, Christine
  Journal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
96. 96
  Nadin, A.; Hattotuwagama, C.; Churcher, I. Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry Angew. Chem., Int. Ed. 2012, 51, 1114– 1122 DOI: 10.1002/anie.201105840
  96
  Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry
  Nadin, Alan; Hattotuwagama, Channa; Churcher, Ian
  Angewandte Chemie, International Edition (2012), 51 (5), 1114-1122, S1114/1-S1114/19CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The pharmaceutical industry remains solely reliant on synthetic chem. methodol. to prep. compds. for small-mol. drug discovery programs. The importance of the physicochem. properties of these mols. in detg. their success in drug development is now well understood, but here, the authors present data suggesting that much synthetic methodol. is unintentionally predisposed to producing mols. with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger nos. of compds. from array techniques are prepd. To address this issue, the authors describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of mols. used to develop new medicines.
97. 97
  Gleeson, M. P.; Hersey, A.; Montanari, D.; Overington, J. Probing the Links between in Vitro Potency, ADMET and Physicochemical Parameters Nat. Rev. Drug Discovery 2011, 10, 197– 208 DOI: 10.1038/nrd3367
  97
  Probing the links between in vitro potency, ADMET and physicochemical parameters
  Gleeson, M. Paul; Hersey, Anne; Montanari, Dino; Overington, John
  Nature Reviews Drug Discovery (2011), 10 (3), 197-208CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  A review. A common underlying assumption in current drug discovery strategies is that compds. with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochem. properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochem. parameters assocd. with high in vitro potency and those assocd. with desirable absorption, distribution, metab., excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on av.); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.
98. 98
  Di Martino, A.; Galli, C.; Gargano, P.; Mandolini, L. Ring-Closure Reactions. Part 23. Kinetics of Formation of Three- to Seven-Membered-Ring N-Tosylazacycloalkanes. The Role of Ring Strain in Small- and Common-Sized-Ring Formation J. Chem. Soc., Perkin Trans. 2 1985, 1345– 1349 DOI: 10.1039/p29850001345
  98
  Ring closure reactions. Part 23. Kinetics of formation of three- to seven-membered-ring N-tosylazacycloalkanes. The role of ring strain in small- and common-sized-ring formation
  Di Martino, Alessandro; Galli, Carlo; Gargano, Patrizia; Mandolini, Luigi
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1985), (9), 1345-9CODEN: JCPKBH; ISSN:0300-9580.
  Rates of cyclization of a series of anions derived from N-p-toluenesulfonyl-ω-bromoalkylamines to N heterocycles with 3-7 members in DMSO-H2O (99:1) were studied. The rates varied markedly with ring size in the order 5 > 3 > 6 > 7 ≈ 4. First-order rate consts. for cyclization were translated into effective molarities (EM) with ref. to an appropriate intermol. model reaction. Comparison of the present results with available literature data on SN2 ring-closure reactions leading to small- and common-size rings reveals that the ease of formation of 3-membered rings is much more structure-dependent than that of the higher homologs. This remarkable behavior is believed to parallel the unique way in which the stability of 3-membered rings is affected by structure. As a rule, the ease of cyclization appears to bear an inverted relationship to the assumed strain energy of the ring product. The apparent opposition of this rule to earlier conclusions in the literature is discussed.
99. 99
  Searles, S.; Nickerson, R. G.; Witsiepe, W. K. Oxetanes. IX. Structural and Solvent Effects in the Reaction of γ–Bromoalcohols with Base J. Org. Chem. 1959, 24, 1839– 1844 DOI: 10.1021/jo01094a001
  There is no corresponding record for this reference.
100. 100
  Searles, S.; Gortatowski, M. J. Cleavage of 3-Bromo-2,2-Dimethyl-1-Propanol by Base J. Am. Chem. Soc. 1953, 75, 3030– 3031 DOI: 10.1021/ja01108a516
  There is no corresponding record for this reference.
101. 101
  Reboul, M. Oxede de Propylene Normal et Poluoxypropylenes Ann. Chim. (Paris) 1878, 14, 495– 497
  There is no corresponding record for this reference.
102. 102
  Picard, P.; Leclercq, D.; Bats, J.-P.; Moulines, J. An Efficient One-Pot Synthesis of Oxetanes from 1,3-Diols Synthesis 1981, 1981, 550– 551 DOI: 10.1055/s-1981-29523
  There is no corresponding record for this reference.
103. 103
  Rosowsky, A.; Tarbell, D. S. Synthesis and Properties of Bicyclic Oxetanes J. Org. Chem. 1961, 26, 2255– 2260 DOI: 10.1021/jo01351a026
  There is no corresponding record for this reference.
104. 104
  Balsamo, A.; Ceccarelli, G.; Crotti, P.; Macchia, F. Mechanism and Stereochemistry of Oxetane Reactions. I. Stereospecific Synthesis of the Diastereoisomeric 2-Phenyl-3-Methyloxetanes and Study of Their Configuration and Conformation by Nuclear Magnetic Resonance Spectroscopy J. Org. Chem. 1975, 40, 473– 476 DOI: 10.1021/jo00892a021
  There is no corresponding record for this reference.
105. 105
  Berkowitz, P. T.; Baum, K. Reactions of 2-Fluoro-2-Nitro-1,3-Propanediol. Trifluoromethanesulfonates and 3-Fluoro-3-Nitrooxetan J. Org. Chem. 1980, 45, 4853– 4857 DOI: 10.1021/jo01312a010
  There is no corresponding record for this reference.
106. 106
  Aftab, T.; Carter, C.; Hart, J.; Nelson, A. A Method for the Stereospecific Conversion of 1,3-Diols into Oxetanes Tetrahedron Lett. 1999, 40, 8679– 8683 DOI: 10.1016/S0040-4039(99)01840-7
  There is no corresponding record for this reference.
107. 107
  Aftab, T.; Carter, C.; Christlieb, M.; Hart, J.; Nelson, A. Stereospecific Conversion of (1R*,3S*)- and (1R*,3R*)-3-Cyclohexyl-1-Phenylpropane-1,3-Diol into the Corresponding 2,4-Disubstituted Oxetanes J. Chem. Soc. Perkin Trans. 1 2000, 711– 722 DOI: 10.1039/a909163g
  There is no corresponding record for this reference.
108. 108
  Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repič, O.; Shapiro, M. J. 1,3- Diastereoselective Reduction of β-Hydroxyketones Utilizing Alkoxydialkylboranes Tetrahedron Lett. 1987, 28, 155– 158 DOI: 10.1016/S0040-4039(00)95673-9
  108
  1,3-syn-Diastereoselective reduction of β-hydroxy ketones utilizing alkoxydialkylboranes
  Chen, Kau Ming; Hardtmann, Goetz E.; Prasad, Kapa; Repic, Oljan; Shapiro, Michael J.
  Tetrahedron Letters (1987), 28 (2), 155-8CODEN: TELEAY; ISSN:0040-4039.
  NaBH4 redn. of 10 β-hydroxy ketones [e.g., BuCH(OH)CH2COBu] complexed with R2BOR1 (R = Et, Bu; R1 = Me, Et, Bu, allyl, CHMe2, CMe3) gives 1,3-syn diols in 98:2 diastereomeric ratio.
109. 109
  Evans, D. A.; Chapman, K. T.; Carreira, E. M. Directed Reduction of Beta-Hydroxy Ketones Employing Tetramethylammonium Triacetoxyborohydride J. Am. Chem. Soc. 1988, 110, 3560– 3578 DOI: 10.1021/ja00219a035
  109
  Directed reduction of β-hydroxy ketones employing tetramethylammonium triacetoxyborohydride
  Evans, D. A.; Chapman, K. T.; Carreira, E. M.
  Journal of the American Chemical Society (1988), 110 (11), 3560-78CODEN: JACSAT; ISSN:0002-7863.
  The mild reducing agent tetramethylammonium triacetoxyborohydride (I) reduces acyclic β-hydroxy ketones to their corresponding anti diols with high diastereoselectivity. α-Alkyl substitution does not significantly affect the stereoselectivity of these redns. In all cases examd., good to excellent yields of diastereomerically homogeneous diols were obtained. The mechanism of these redns. involves an acid-promoted ligand exchange of acetate for substrate alc. by the triacetoxyborohydride anion. The resultant hydride intermediate, presumably an alkoxydiacetoxyborohydride, reduces proximal ketones by intramol. hydride delivery. Ketones, β-keto esters, and β-diketones are not reduced by I in the absence of a suitably disposed hydroxyl group. Indeed both cyclic and acyclic β-hydroxy ketones may be conveniently reduced in a solvent of 1:1 acetone-acetic acid. Hydroxy diketo ester II undergoes sequential diastereoselective redns. with tetramethylammonium triacetoxyborohydride to afford a 50% isolated yield of anti-anti triol ester III in a unique stereopropagating reaction.
110. 110
  Soai, K.; Niwa, S.; Yamanoi, T.; Hikima, H.; Ishizaki, M. Asymmetric Synthesis of 2-Aryl Substituted Oxetanes by Enantioselective Reduction of β-Halogenoketones Using Lithium Borohydride Modified with N,N′-Dibenzoylcystine J. Chem. Soc., Chem. Commun. 1986, 1018– 1019 DOI: 10.1039/C39860001018
  110
  Asymmetric synthesis of 2-aryl substituted oxetanes by enantioselective reduction of β-halo ketones using lithium borohydride modified with N,N'-dibenzoylcystine
  Soai, Kenso; Niwa, Seiji; Yamanoi, Takashi; Hikima, Hitoshi; Ishizaki, Miyuki
  Journal of the Chemical Society, Chemical Communications (1986), (13), 1018-19CODEN: JCCCAT; ISSN:0022-4936.
  Stereoselective redn. of p-RC6H4COCR12CH2Cl (R = H, F, R1 = H; R = H, R1 = Me) with LiBH4, Me3COH, and (R,R)-N,N'-dibenzoylcystine in THF at -78 to -30° for 9 h gave the corresponding (R)-p-RC6H4CH(OH)CR12CH2Cl which were cyclized with KOH to give the corresponding oxetanes I in 79-89% enantiomeric excess.
111. 111
  Lo, M. M.-C.; Fu, G. C. Applications of Planar-Chiral Heterocycles in Enantioselective Catalysis: Cu(I)/bisazaferrocene-Catalyzed Asymmetric Ring Expansion of Oxetanes to Tetrahydrofurans Tetrahedron 2001, 57, 2621– 2634 DOI: 10.1016/S0040-4020(01)00082-5
  111
  Applications of planar-chiral heterocycles in enantioselective catalysis: Cu(I)/bisazaferrocene-catalyzed asymmetric ring expansion of oxetanes to tetrahydrofurans
  Lo, M. M.-C.; Fu, G. C.
  Tetrahedron (2001), 57 (13), 2621-2634CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
  A planar-chiral, C2-sym. bisazaferrocene ligand is shown to control the stereochem. of Cu(I)-catalyzed ring expansions of oxetanes to tetrahydrofurans.
112. 112
  Brown, H. C.; Ramachandran, V. P. Asymmetric Reduction with Chiral Organoboranes Based on Alpha-Pinene Acc. Chem. Res. 1992, 25, 16– 24 DOI: 10.1021/ar00013a003
  There is no corresponding record for this reference.
113. 113
  Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Opening of Substituted Oxetanes with H₂O₂ and Alkyl Hydroperoxides: Stereoselective Approach to 3-Peroxyalcohols and 1,2,4-Trioxepanes Org. Lett. 2002, 4, 4591– 4593 DOI: 10.1021/ol0265259
  113
  Opening of Substituted Oxetanes with H2O2 and Alkyl Hydroperoxides: Stereoselective Approach to 3-Peroxyalcohols and 1,2,4-Trioxepanes
  Dussault, Patrick H.; Trullinger, Tony K.; Noor-e-Ain, Farhana
  Organic Letters (2002), 4 (26), 4591-4593CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  Lewis acid-catalyzed ring opening of optically active oxetanes I [R1 = R3 = R4 = H, R2 = n-hexyl; R1 = Me, R2 = n-C16H33, Me2C:CHCH2CH2, Me2CH(CH2)3; R3, R4 = H, Me] by hydrogen peroxide proceeded regioselectively and with good to moderate stereoselectivity to furnish enantiomerically enriched 3-hydroperoxyalkanols II (R5 = H). The analogous opening using alkyl hydroperoxides R5O2H (R5 = Me3C, cumyl, tetrahydropyranyl) furnished the corresponding 3-peroxyalkanols II. II (R1 = Me; R2 = n-C16H33, Me2C:CHCH2CH2; R3 = R4 = R5 = H) were easily converted into enantiomerically enriched 1,2,4-trioxepanes III, the building blocks for antimalarials.
114. 114
  Roy, B. G.; Roy, A.; Achari, B.; Mandal, S. B. A Simple One-Pot Entry to Cyclic Ethers of Varied Ring Sizes from Diols via Phosphonium Ion Induced Iodination and Base Catalyzed Williamson Etherification Tetrahedron Lett. 2006, 47, 7783– 7787 DOI: 10.1016/j.tetlet.2006.08.090
  There is no corresponding record for this reference.
115. 115
  Kawahata, Y.; Takatsuto, S.; Ikekawa, N.; Murata, M.; Omura, S. Synthesis of a New Amino Acid- Antibiotic, Oxetin and Its Three Stereoisomers Chem. Pharm. Bull. 1986, 34, 3102– 3110 DOI: 10.1248/cpb.34.3102
  There is no corresponding record for this reference.
116. 116
  Wolfrom, M. L.; Hanessian, S. The Reaction of Free Carbonyl Sugar Derivatives with Organometallic Reagents. I. 6-Deoxy-L-idose and Derivatives J. Org. Chem. 1962, 27, 1800– 1804 DOI: 10.1021/jo01052a076
  116
  The reaction of free carbonyl sugar derivatives with organometallic reagents. I. 6-Deoxy-L-idose and derivatives
  Wolfrom, M. L.; Hanessian, S.
  Journal of Organic Chemistry (1962), 27 (), 1800-4CODEN: JOCEAH; ISSN:0022-3263.
  A stereospecific synthesis of 6-deoxy-L-idose (I) is described. It is shown that I changes to 6-deoxy-L-sorbose (II) in the presence of acid, but is otherwise stable when prepd. under neutral conditions. Reaction of 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose (III) with p-nitrobenzoyl chloride in pyridine afforded 3-O-benzyl-1,2-O-isopropylidene-5,6-di-O-(p-nitrobenzoyl)-α-D-glucofuranose (IV), m. 116-17° (Me2CO-petr. ether), [α]25D -22° (c 1.5, Me2CO). A suspension of 200 g. Pb(OAc)4 in 1.5 l. C6H6 was added gradually to 100 ml. C6H6 contg. 94 g. III, the mixt. warmed several min., filtered, the filtrate evapd. to a sirup dissolved in Et2O filtered, and the filtrate evapd. to give 79 g. sirup (92%). Distn. in a Hickman mol. pot. still and collecting the fraction, b0.07 150-5°, gave 55 g. 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (V), [α]25D -86.5° (c 2.7, EtOH-free CHCl3), strongly reducing to Fehling soln. and giving a Schiff test; V treated with semicarbazide-HCl in EtOH-H2O gave 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose semicarbazone (VI), m. 177-8°, [α]25D -50° (c 1.48, EtOH). V hydrogenated 4 hrs. over Pd-C at 65° and 400 lb./sq. in. gave 0.94 g. 1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (VII) as a sirup showing both OH and C:O absorption but lacking Ph absorption in the infrared spectrum; C:O peak diminished slightly on standing at room temp. one week; semicarbazone (VIII) m. 208-9°. V (10 g.) in 70 ml. Et2O was added dropwise over 2 hrs. to a refluxing Grignard soln. prepd. from 10.5 ml. MeI and 4.5 g. Mg turnings in 150 ml. Et2O, the mixt. refluxed another 30 min., cooled, added dropwise to a cold satd. soln. of NH4Cl (200 ml.) with vigorous stirring, the soln. extd. with Et2O, and the latter dried and evapd. under reduced pressure to a sirup that crystd. to give 6.65 g. 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (IX). The aq. soln. was evapd. to dryness, the residue extd. with CHCl3, and the soln. dried and evapd. to give 0.35 g. IX, total yield 7 g.; recrystn. from petr. ether contg. a trace of MeOH and again from Et2O-petr. ether gave 6.2 g. IX, m. 93-4°, [α]25D -63.5° (c 1.3, CHCl3). Extensive search of mother liquors from IX failed to locate any 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (X). IX (0.3 g.) in 2 ml. pyridine treated with 0.2 ml. MeSO2Cl and 2 ml. CHCl3, the mixt. poured in ice-water after standing 16 hrs. at room temp., and the solid filtered off and washed with Et2O-petr. ether (1:5) gave 0.28 g. 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-5-O-methylsulfonyl-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XI), m. 99-100° (Et2O), [α]25D -60° (c 1, CHCl3). IX (2.5 g.) in 50 ml. EtOH hydrogenated over 0.25 g. Pd-C under 300 lb./sq. in. at 65-8° 4 hrs. (the reaction failed at 28 lb./sq. in. and room temp. 24 hrs.), gave a sirup which evapd. on standing. The crystals washed with cold Et2O gave 1.1 g. 6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XII), m. 88-9°, [α]20D -7° (c 3.4, CHCl3). Acetylation of 0.15 g. XII in 1 ml. Ac2O gave after trituration of an initial sirup with Et2O-petr. ether, 0.18 g. 3,5-di-O-acetyl-6-deoxy-1,2-O-isopropylidene-β-L-ido-(L-glycero-α-D-xylo-hexo)furanose (XIII), m. 122-3° [α]23D -27° (c 2, CHCl3). IX (2.94 g.) in 12 ml. MeOH contg. 4.41 ml. N H2SO4 stirred at 70° 4 hrs., the soln. evapd., the residue in 3 ml. H2O heated an addnl. hr., the soln. neutralized with BaCO3, filtered through decolorizing C, and the filtrate evapd. gave 3-O-benzyl-6-deoxy-L-idose (XIV) as a sirup, [α]23D -11° (c 4, EtOH), Rf 0.78 in 4:1:5 BuOH-EtOH-H2O. A soln. contg. 0.85 g. XIV, 0.3 g. NaOAc, and 0.76 g. 1-benzyl-1-phenylhydrazine-HCl in 25 ml. EtOH was refluxed 3 hrs., decolorized with C, filtered, the filtrate evapd., and the residue extd. with CHCl3, washed with H2O, dried, and evapd. to a sirup that crystd. from Et2O-petr. ether to give 1.1 g. 3-O-benzyl-6-deoxy-L-idose benzylphenylhydrazone (XV), m. 120-1° (EtOH), [α]25D 44° (c 1, EtOH). XIV (0.5 g.) was heated 2 hrs. with 1.5 g. NaOAc and 2 g. PhNHNH2.HCl in 10 ml. H2O in a boiling water bath, the solvent decanted, and the residue dissolved in C6H6 and dild. with petr. ether to give 3-O-benzyl-6-deoxy-L-xylo-hexose phenylosazone (X-VI). Recrystn. from EtOH-H2O gave 0.6 g. XVI, m. 95-6°, [α]25D 36° (c 0.3, 2:3 pyridine-EtOH). XII (0.13 g.) in 0.14 ml. 0.5% H2SO4 was heated 2 hrs. at 70°, the soln. neutralized with BaCO3, treated with C, filtered, and the filtrate evapd. to a sirup which showed three spots, Rf 0.22 (zone A), 0.32 (zone B), and 0.44 (zone C) when chromatographed on paper in 4:1:5 BuOH-EtOH-H2O. Sepn. on paper sheets, elution of the resp. zones with water, and freeze-drying gave 4.9 mg. (zone A), not further studied; 12.8 mg. (zone B), and 70 mg. (zone C, II), [α]25D -24° (c 0.7, H2O). XIV (0.1 g.) in 25 ml. EtOH hydrogenated 4.5 hrs. over 10 mg. Pd-C at 500 lb./sq. in. and 65°, the mixt. filtered, and the filtrate concd. gave 80 mg. of a sirup, I, [α]25 -1.9° (c 2.5, H2O), Rf 0.32 (identical with material from zone B). Material from zone C and I (from hydrogenolysis of XIV) gave the same 6-deoxy-L-xylo-hexose phenylosazone (XVI), m. 160-6° (decompn.). I (15 mg.) (from hydrogenolysis of XIV) heated 3 hrs. in H2O contg. Amberlite IR-120 (H+) resin and the samples spotted at time intervals on paper and chromatographed, showed a new spot, C, identical with II, in addn. to the original spot B with as little as 5 min. heating.
117. 117
  Nishiyama, S.; Yamamura, S.; Kato, K.; Takita, T. A Total Synthesis of Oxetanocin, a Novel Nucleoside with an Oxetane Ring Tetrahedron Lett. 1988, 29, 4743– 4746 DOI: 10.1016/S0040-4039(00)80596-1
  117
  A total synthesis of oxetanocin, a novel nucleoside with an oxetane ring
  Nishiyama, Shigeru; Yamamura, Shosuke; Kato, Kuniki; Takita, Tomohisa
  Tetrahedron Letters (1988), 29 (37), 4743-6CODEN: TELEAY; ISSN:0040-4039.
  Oxetanocin (I) has been synthesized starting from cis-2-butene-1,4-diol through α- or β-D-oxetanosyl acetate which has an α-(Me oxalyloxy)methyl group at C2-position.
118. 118
  Nishiyama, S.; Yamamura, S.; Kato, K.; Takita, T. Synthetic Studies on Oxetanocin, a Novel Nucleoside with an Oxetane Ring Synthesis of Some Chiral D-Oxetanosyl Acylates Tetrahedron Lett. 1988, 29, 4739– 4742 DOI: 10.1016/S0040-4039(00)80595-X
  118
  Synthetic studies on oxetanocin, a novel nucleoside with an oxetane ring. Synthesis of some chiral D-oxetanosyl acylates
  Nishiyama, Shigeru; Yamamura, Shosuke; Kato, Kuniki; Takita, Tomohisa
  Tetrahedron Letters (1988), 29 (37), 4739-42CODEN: TELEAY; ISSN:0040-4039.
  Some chiral D-oxetanosyl acylates, e.g., I, promising synthetic precursors of oxetanocin (II), have been synthesized from D-glucose and cis-2-butene-1,4-diol, the most important step being Baeyer-Villiger oxidn. of the carbonyl group attached to C-1 of the oxetanes.
119. 119
  Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L. The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol J. Am. Chem. Soc. 1997, 119, 2757– 2758 DOI: 10.1021/ja963539z
  119
  The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol
  Wender, Paul A.; Badham, Neil F.; Conway, Simon P.; Floreancig, Paul E.; Glass, Timothy E.; Houze, Jonathan B.; Krauss, Nancy E.; Lee, Daesung; Marquess, Daniel G.; McGrane, Paul L.; Meng, Wei; Natchus, Michael G.; Shuker, Anthony J.; Sutton, James C.; Taylor, Richard E.
  Journal of the American Chemical Society (1997), 119 (11), 2757-2758CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A novel strategy based on an aldol cyclization which allows for the conversion of a general taxane precursor into the highly promising chemotherapeutic agent Taxol was described. This strategy allows for the synthesis of baccatins I (R = H, acetyl) starting from taxane precursor II [R1 = Si(CHMe2)3], which is available starting from (+)-verbenone. Conversion of I to Taxol has been achieved employing known three and four steps sequences, resp. This represents the shortest reported synthesis of Taxol and provides even more concise access to key analogs.
120. 120
  Doi, T.; Fuse, S.; Miyamoto, S.; Nakai, K.; Sasuga, D.; Takahashi, T. A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer Chem. - Asian J. 2006, 1, 370– 383 DOI: 10.1002/asia.200600156
  120
  A formal total synthesis of taxol aided by an automated synthesizer
  Doi, Takayuki; Fuse, Shinichiro; Miyamoto, Shigeru; Nakai, Kazuoki; Sasuga, Daisuke; Takahashi, Takashi
  Chemistry - An Asian Journal (2006), 1 (3), 370-383CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A 36-step synthesis was carried out in automated synthesizers to provide a synthetic key intermediate of taxol. A key step involved a microwave-assisted alkylation reaction to construct the ABC ring system from an AC precursor. Subsequent formation of the D ring afforded (±)-baccatin III, a well-known precursor of taxol.
121. 121
  Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Total Synthesis of Taxol Nature 1994, 367, 630– 634 DOI: 10.1038/367630a0
  121
  Total synthesis of taxol
  Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; et al.
  Nature (London, United Kingdom) (1994), 367 (6464), 630-4CODEN: NATUAS; ISSN:0028-0836.
  The total synthesis of taxol (I) from the benzofuranone II by a convergent strategy, which opens a chem. pathway for the prodn. of both I and a variety of designed taxoids is reported.
122. 122
  Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M. Asymmetric Total Synthesis of Taxol Chem. - Eur. J. 1999, 5, 121– 161 DOI: 10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.3.CO;2-F
  122
  Asymmetric total synthesis of taxol
  Mukaiyama, Teruaki; Shiina, Isamu; Iwadare, Hayato; Saitoh, Masahiro; Nishimura, Toshihiro; Ohkawa, Naoto; Sakoh, Hiroki; Nishimura, Koji; Tani, Yu-Ichirou; Hasegawa, Masatoshi; Yamada, Koji; Saitoh, Katsuyuki
  Chemistry - A European Journal (1999), 5 (1), 121-161CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
  The asym. total synthesis of taxol was achieved by way of B to BC to ABC to ABCD ring construction. Optically active 8-membered ring enones corresponding to the B ring of taxol were synthesized in high yields from the linear precursors via intramol. aldol cyclization using SmI2. The optically active linear polyoxy compds. were obtained by way of diastereoselective aldol reaction between the protected 2,2-dimethylpentanal and the (Z)-ketene silyl acetal catalyzed by MgBr2·OEt2. This chiral pentanal was synthesized either by asym. aldol reaction of achiral aldehyde and the (Z)-ketene silyl acetal by a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde derived from L-serine and the lithium enolate derived from Me isobutyrate. Optically active bicyclo[6.4.0]dodecanone I, corresponding to the BC ring system of taxol, was prepd. from 8-membered ring enone in high yield by stereoselective Michael addn. and successive intramol. aldol cyclization. Baccatin III, the ABCD ring system of taxol, was efficiently synthesized from the BC ring system I by successive construction of the A and D rings by intramol. pinacol coupling cyclization, introduction of the C-13 hydroxyl group and an oxetane-forming reaction. The total synthesis of taxol was accomplished by dehydration condensation between a protected N-benzoylphenylisoserine and 7-TES baccatin III, prepd. from baccatin III. Taxol side chains and optically active protected N-benzoylphenylisoserines, were synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether derived from S-Et benzyloxyethanethioate.
123. 123
  Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I. Enantioselective Total Synthesis of (−)-Taxol J. Am. Chem. Soc. 2000, 122, 3811– 3820 DOI: 10.1021/ja9939439
  123
  Enantioselective Total Synthesis of (-)-Taxol
  Kusama, Hiroyuki; Hara, Ryoma; Kawahara, Shigeru; Nishimori, Toshiyuki; Kashima, Hajime; Nakamura, Nobuhito; Morihira, Koichiro; Kuwajima, Isao
  Journal of the American Chemical Society (2000), 122 (16), 3811-3820CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde (I) with the arom. C-ring fragment 2-bromobenzaldehyde dibenzylacetal followed by Lewis acid mediated eight-membered B-ring cyclization gave the desired ABC endo-tricarbocycle (II). The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene deriv., which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol (III) stereoselectively. For introduction of the C19-Me, the cyclopropyl ketone (IV) was prepd. via cyclopropanation of the C-ring allylic alc. or conjugate addn. of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate (V) contg. the C19-Me group. Regioselective transformation of three hydroxyl groups of V, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-oxygen functionality afforded a precursor for D-ring construction. Dihydroxylation of the allyl chloride moiety followed by basic treatment of the resulting diol gave a fully functionalized taxol skeleton (VI). Functional group manipulation of VI including attachment of the C13 side chain provided (-)-taxol.
124. 124
  Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. Enantioselective Total Synthesis of Taxol J. Am. Chem. Soc. 1998, 120, 12980– 12981 DOI: 10.1021/ja9824932
  124
  Enantioselective Total Synthesis of Taxol
  Morihira, Koichiro; Hara, Ryoma; Kawahara, Shigeru; Nishimori, Toshiyuki; Nakamura, Nobuhito; Kusama, Hiroyuki; Kuwajima, Isao
  Journal of the American Chemical Society (1998), 120 (49), 12980-12981CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An enantioselective total synthesis of (-)-taxol was achieved. The synthetic route is highlighted by (1) originally developed B-ring cyclization, (2) introduction of the C19-Me via reductive cleavage of the cyclopropyl ketone I, and (3) isomerization of the resulting enol to the ketone.
125. 125
  Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H. First Total Synthesis of Taxol. 1. Functionalization of the B Ring J. Am. Chem. Soc. 1994, 116, 1597– 1598 DOI: 10.1021/ja00083a066
  125
  First total synthesis of taxol. 1. Functionalization of the B ring
  Holton, Robert A.; Somoza, Carmen; Kim, Hyeong Baik; Liang, Feng; Biediger, Ronald J.; Boatman, P. Douglas; Shindo, Mitsuru; Smith, Chase C.; Kim, Soekchan; et al.
  Journal of the American Chemical Society (1994), 116 (4), 1597-8CODEN: JACSAT; ISSN:0002-7863.
  Beginning stages of a total synthesis of the anti-tumor agent taxol were described. These stages result in the prepn. of an intermediate having three rings in which 6 stereocenters of the natural product are set. The key feature of this part of the total synthesis is control of conformation and reactivity in the bicyclo[5.3.1]undecane ring system. Thus, the diol I, a taxusin intermediate readily available from camphor, was transformed to the lactone carbonate II in 12 steps and 40% overall yield.
126. 126
  Holton, R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H. First Total Synthesis of Taxol. 2. Completion of the C and D Rings Robert J. Am. Chem. Soc. 1994, 116, 1599– 1600 DOI: 10.1021/ja00083a067
  There is no corresponding record for this reference.
127. 127
  Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. Total Synthesis of Baccatin III and Taxol J. Am. Chem. Soc. 1996, 118, 2843– 2859 DOI: 10.1021/ja952692a
  127
  Total Synthesis of Baccatin III and Taxol
  Danishefsky, Samuel J.; Masters, John J.; Young, Wendy B.; Link, J. T.; Snyder, Lawrence B.; Magee, Thomas V.; Jung, David K.; Isaacs, Richard C. A.; Bornmann, William G.; et al.
  Journal of the American Chemical Society (1996), 118 (12), 2843-59CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An intramol. Heck reaction (diene I to pentacycle II) serves as the key step in the total synthesis of the titled compds. III (R = H, R2). The synthetic route is based on utilizing the Wieland-Miescher ketone (IV) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to A ring precursor, 2,2,4-trimethyl-1,3-cyclohexanedione. Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
128. 128
  Fukaya, K.; Kodama, K.; Tanaka, Y.; Yamazaki, H.; Sugai, T.; Yamaguchi, Y.; Watanabe, A.; Oishi, T.; Sato, T.; Chida, N. Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis Org. Lett. 2015, 17, 2574– 2577 DOI: 10.1021/acs.orglett.5b01174
  128
  Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis
  Fukaya, Keisuke; Kodama, Keisuke; Tanaka, Yuta; Yamazaki, Hirohisa; Sugai, Tomoya; Yamaguchi, Yu; Watanabe, Ami; Oishi, Takeshi; Sato, Takaaki; Chida, Noritaka
  Organic Letters (2015), 17 (11), 2574-2577CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-D-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate (I). A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.
129. 129
  Hirai, S.; Utsugi, M.; Iwamoto, M.; Nakada, M. Formal Total Synthesis of (−)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation Chem. - Eur. J. 2015, 21, 355– 359 DOI: 10.1002/chem.201404295
  129
  Formal Total Synthesis of (-)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation
  Hirai, Sho; Utsugi, Masayuki; Iwamoto, Mitsuhiro; Nakada, Masahisa
  Chemistry - A European Journal (2015), 21 (1), 355-359CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A formal total synthesis of (-)-taxol by a convergent approach utilizing Pd-catalyzed intramol. alkenylation is described. Formation of the eight-membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd-catalyzed intramol. alkenylation of a Me ketone affording the cyclized product in excellent yield (97%), indicating the high efficiency of the Pd-catalyzed intramol. alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5-hydride shift, generating the C3 stereogenic center and subsequently forming the C1-C2 benzylidene, was discovered and utilized in the prepn. of a substrate for the Pd-catalyzed reaction.
130. 130
  Zefirova, O. N.; Nurieva, E. V.; Lemcke, H.; Ivanov, A. A.; Zyk, N. V.; Weiss, D. G.; Kuznetsov, S. A.; Zefirov, N. S. Design, Synthesis and Bioactivity of Simplified Taxol Analogues on the Basis of bicyclo[3.3.1]nonane Derivatives Mendeleev Commun. 2008, 18, 183– 185 DOI: 10.1016/j.mencom.2008.07.003
  130
  Design, synthesis and bioactivity of simplified taxol analogs on the basis of bicyclo[3.3.1]nonane derivatives
  Zefirova, Olga N.; Nurieva, Evgeniya V.; Lemcke, Heiko; Ivanov, Andrei A.; Zyk, Nikolai V.; Weiss, Dieter G.; Kuznetsov, Sergei A.; Zefirov, Nikolai S.
  Mendeleev Communications (2008), 18 (4), 183-185CODEN: MENCEX; ISSN:0959-9436. (Elsevier B.V.)
  Four specially designed bicyclo[3.3.1]nonane derivs. I [R = Ph, R1 = H, R2 = H; R = Ph, R1 = OCOPh, R2 = H; R = Ph, R1 = H, R2 = CH2OAc; R = OCMe3, R1 = H, R2 = 3-oxetanyloxycarbonyl] were synthesized and found to be cytotoxic at micromolar concns. against A549 human lung carcinoma cells and to cause slight non-specific tubulin aggregation.
131. 131
  Fuji, K.; Watanabe, Y.; Ohtsubo, T.; Nuruzzaman, M.; Hamajima, Y.; Kohno, M. Synthesis of Extremely Simplified Compounds Possessing the Key Pharmacophore Units of Taxol, Phenylisoserine and Oxetane Moieties Chem. Pharm. Bull. 1999, 47, 1334– 1337 DOI: 10.1248/cpb.47.1334
  131
  Synthesis of extremely simplified compounds possessing the key pharmacophore units of taxol, phenylisoserine and oxetane moieties
  Fuji, Kaoru; Watanabe, Yukari; Ohtsubo, Tadamune; Nuruzzaman, Mohammad; Hamajima, Yoshio; Kohno, Michiaki
  Chemical & Pharmaceutical Bulletin (1999), 47 (9), 1334-1337CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
  Straight-chain compds. having a phenylisoserine unit and an oxetane ring at the α- and ω-position, resp., were prepd. as simplified analogs of taxol. Their most stable conformations were calcd. using mol. mechanics. None of these compds. showed promising tubulin inhibitory activity.
132. 132
  Chen, X.-X.; Gao, F.; Wang, Q.; Huang, X.; Wang, D. Design, Synthesis and Biological Evaluation of Paclitaxel-Mimics Possessing Only the Oxetane D-Ring and Side Chain Structures Fitoterapia 2014, 92, 111– 115 DOI: 10.1016/j.fitote.2013.10.015
  132
  Design, synthesis and biological evaluation of paclitaxel-mimics possessing only the oxetane D-ring and side chain structures
  Chen, Xing-Xiu; Gao, Feng; Wang, Qi; Huang, Xing; Wang, Dan
  Fitoterapia (2014), 92 (), 111-115CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)
  Two spiro paclitaxel-mimics consisting only of an oxetane D-ring and a C-13 side chain were designed and synthesized on the basis of anal. of structure-activity relationships of paclitaxel. In vitro microtubule-stabilizing and antiproliferative assays indicated a moderate weaker activity of the mimics than paclitaxel, but which still represented the first example of simplified paclitaxel analogs with significant antitumor activity.
133. 133
  Ye, Y.; Zheng, C.; Fan, R. Solvent-Controlled Oxidative Cyclization for Divergent Synthesis of Highly Functionalized Oxetanes and Cyclopropanes Org. Lett. 2009, 11, 3156– 3159 DOI: 10.1021/ol9012102
  133
  Solvent-Controlled Oxidative Cyclization for Divergent Synthesis of Highly Functionalized Oxetanes and Cyclopropanes
  Ye, Yang; Zheng, Chen; Fan, Renhua
  Organic Letters (2009), 11 (14), 3156-3159CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  An efficient solvent-controlled oxidative cyclization of Michael adducts of malonates with chalcones with the combination of iodosobenzene and tetrabutylammonium iodide is reported. Highly functionalized oxetanes and cyclopropanes were divergently synthesized in moderate to excellent yields with high diastereoselectivity.
134. 134
  Miao, C.-B.; Zhang, M.; Tian, Z.-Y.; Xi, H.-T.; Sun, X.-Q.; Yang, H.-T. Base-Controlled Selective Conversion of Michael Adducts of Malonates with Enones in the Presence of Iodine J. Org. Chem. 2011, 76, 9809– 9816 DOI: 10.1021/jo201879t
  There is no corresponding record for this reference.
135. 135
  Davies, A. T.; Slawin, A. M. Z.; Smith, A. D. Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes Chem. - Eur. J. 2015, 21, 18944– 19848 DOI: 10.1002/chem.201504256
  135
  Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes
  Davies, Alyn T.; Slawin, Alexandra M. Z.; Smith, Andrew D.
  Chemistry - A European Journal (2015), 21 (52), 18944-18948CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The N-heterocyclic carbene (NHC) catalyzed redox formal [2+2] cycloaddn. between α-aroyloxyaldehydes and perfluoroketones, followed by ring-opening in situ delivers a variety of perfluorinated β-hydroxycarbonyl compds. in good yield, and excellent diastereoselectivity and enantioselectivity. Through a reductive work-up and subsequent cyclization, this protocol offers access to highly substituted fluorinated oxetanes in two steps and in high ee. Under optimized conditions the synthesis of the target compds. was achieved using (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazinium chloride as a catalyst. Starting materials included 2,2,3,3,3-pentafluoro-1-phenyl-1-propanone 2,2,3,3,4,4,5,5,5-nonafluoro-1-phenyl-1-pentanone, trifluoroacetone, 2-[(4-nitrobenzoyl)oxy]propanal, α-[(4-nitrobenzoyl)oxy]benzenepropanal and amine derivs. Oxetane derivs. included 3-alkyl-2-(phenyl)-2-(perfluoroalkyl)oxetane.
136. 136
  Behrendt, J. M.; Bala, K.; Golding, P.; Hailes, H. C. Oxetane Synthesis via Cyclisation of Aryl Sulfonate Esters on Polystyrene and PEG Polymeric Supports Tetrahedron Lett. 2005, 46, 643– 645 DOI: 10.1016/j.tetlet.2004.11.138
  There is no corresponding record for this reference.
137. 137
  Vigo, D.; Stasi, L.; Gagliardi, S. Synthesis of 3,3-Disubstituted Oxetane Building Blocks Tetrahedron Lett. 2011, 52, 565– 567 DOI: 10.1016/j.tetlet.2010.11.118
  There is no corresponding record for this reference.
138. 138
  Boyd, S.; Davies, C. D. A New and Versatile Synthesis of 3-Substituted Oxetan-3-yl Methyl Alcohols Tetrahedron Lett. 2014, 55, 4117– 4119 DOI: 10.1016/j.tetlet.2014.06.024
  There is no corresponding record for this reference.
139. 139
  Searles, S.; Nickerson, R. G.; Witsiepe, W. K. Oxetanes. IX. Structural and Solvent Effects in the Reaction of γ-Bromoalcohols with Base J. Org. Chem. 1959, 24, 1839– 1844 DOI: 10.1021/jo01094a001
  There is no corresponding record for this reference.
140. 140
  Davis, O. A.; Bull, J. A. Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-Catalyzed O-H Insertion and C-C Bond-Forming Cyclization Angew. Chem., Int. Ed. 2014, 53, 14230– 14234 DOI: 10.1002/anie.201408928
  140
  Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-Catalyzed O-H Insertion and C-C Bond-Forming Cyclization
  Davis, Owen A.; Bull, James A.
  Angewandte Chemie, International Edition (2014), 53 (51), 14230-14234CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl-substituted oxetanes and fused oxetane bicycles. Enantioenriched alcs. provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chem.
141. 141
  Nagai, M.; Kato, K.; Takita, T.; Nishiyama, S.; Yamamura, S. A Facile and Practical Synthesis of the Derivatives of 1-O-Acetyl-2-Deoxy-2-Hydroxymethyl-D-Erythrooxetanose, a Key Sugar Moiety for the Synthesis of Oxetanosyl-N-Glycoside Tetrahedron Lett. 1990, 31, 119– 120 DOI: 10.1016/S0040-4039(00)94349-1
  141
  A facile and practical synthesis of the derivatives of 1-O-acetyl-2-deoxy-2-hydroxymethyl-D-erythrooxetanose, a key sugar moiety for the synthesis of oxetanosyl-N-glycoside
  Nagai, Masashi; Kato, Kuniki; Takita, Tomohisa; Nishiyama, Shigeru; Yamamura, Shosuke
  Tetrahedron Letters (1990), 31 (1), 119-20CODEN: TELEAY; ISSN:0040-4039.
  Intramol. cyclization of the epoxy-alc. I with KOH in aq. DMSO gave predominantly the oxetane II (R = CH2Ph, R1 = CHMeOH), which could be transformed into 1-O-acetyl-D-oxetanose II (R = Bz, R1 = OAc).
142. 142
  Nagai, M.; Kato, K.; Takita, T.; Nishiyama, S.; Yamamura, S. An Improved, Practical Synthesis of the Derivatives of 1-O-Acetyl-2- Deoxy-2-Hydroxymethyl-D-Erythrooxetanose, a Key Sugar Moiety for the Synthesis of Oxetanosyl-N-Glycoside Tetrahedron 1990, 46, 7703– 7710 DOI: 10.1016/S0040-4020(01)90066-3
  There is no corresponding record for this reference.
143. 143
  Chung, S.-K.; Ban, S. H.; Kim, S. H.; Woo, S. H. Review: Design, Synthesis and Bioactivities of Heterocyclic Lipids as Platelet Activating Factor Antagonists Korean J. Med. Chem. 1996, 6 (2) 294– 302
  143
  Design, synthesis and bioactivities of heterocyclic lipids as platelet activating factor antagonists
  Chung, Sung-Kee; Ban, Su Ho; Kim, Si Hwan; Woo, Soon Hyung
  Korean Journal of Medicinal Chemistry (1996), 6 (2), 294-302CODEN: KJMCE7; ISSN:1225-0058. (Korean Chemical Society)
  Title compds. such as I [X = (CH2)n, n = 1-4; O, AcN], II [X = CH2CH2, O, S; T = CO; n = 4, 5; N(Het) = pyridine, thiazole, quinoline], and III (X = CH2, O, S, NAc, NBz; Y = Cl, I) were prepd. and tested for their ability to displace [3H]-PAF from its receptor in rabbit platelet membranes and to inhibit PAF-induced aggregation of rabbit platelets.
144. 144
  Wishka, D. G.; Beagley, P.; Lyon, J.; Farley, K. A.; Walker, D. P. A Concise Synthesis of 6-Oxa-3-azabicyclo[31.1]heptane Hydrotosylate Synthesis 2011, 2011, 2619– 2624 DOI: 10.1055/s-0030-1260116
  There is no corresponding record for this reference.
145. 145
  Birman, V. B.; Danishefsky, S. J. The Total Synthesis of (±)-Merrilactone A J. Am. Chem. Soc. 2002, 124, 2080– 2081 DOI: 10.1021/ja012495d
  145
  The total synthesis of (±)-merrilactone A
  Birman, Vladimir B.; Danishefsky, Samuel J.
  Journal of the American Chemical Society (2002), 124 (10), 2080-2081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The total synthesis of the (±)-merrilactone A (I) has been accomplished in 20 steps. The key step is a free radical cyclization of vinyl bromide II [R = CH2CH2C(:CH2)Br] to afford III. The synthesis also features an efficient Diels-Alder reaction of 2,3-dimethylmaleic anhydride with 1-(tert-butyldimethylsiloxy)-butadiene. The oxetane moiety of I is fashioned via a Payne-like rearrangement of a hydroxyepoxide (see IV → I).
146. 146
  Inoue, M.; Sato, T.; Hirama, M. Asymmetric Total Synthesis of (−)-Merrilactone A: Use of a Bulky Protecting Group as Long-Range Stereocontrolling Element Angew. Chem., Int. Ed. 2006, 45, 4843– 4848 DOI: 10.1002/anie.200601358
  146
  Asymmetric total synthesis of (-)-merrilactone A: use of a bulky protecting group as long-range stereocontrolling element
  Inoue, Masayuki; Sato, Takaaki; Hirama, Masahiro
  Angewandte Chemie, International Edition (2006), 45 (29), 4843-4848CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Designer elegance: The transannular aldol reaction of a cyclooctene diketone is the key step in this total synthesis of the natural enantiomer of merrilactone A, I. The configuration of the two stereocenters generated in the formation of the central bicyclo[3.3.0]octane framework of the natural product was established using a specially designed bulky protecting group.
147. 147
  Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.; Zhai, H. Total Synthesis of (±)-Merrilactone A Angew. Chem., Int. Ed. 2012, 51, 5897– 5899 DOI: 10.1002/anie.201200378
  147
  Total Synthesis of (±)-Merrilactone A
  Chen, Jianwei; Gao, Peng; Yu, Fangmiao; Yang, Yang; Zhu, Shizheng; Zhai, Hongbin
  Angewandte Chemie, International Edition (2012), 51 (24), 5897-5899, S5897/1-S5897/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An efficient total synthesis of (±)-Merrilactone A (I) was accomplished in fifteen reaction steps for the shortest sequence from an allyl alc. Key features include Johnson-Claisen rearrangement and the subsequent deprotection-lactonization to generate the A ring, intramol. hetero-Pauson-Khand reaction to construct the B and D rings in one step, and vinylogous Mukaiyama-Michael reaction and reductive carbonyl-alkene coupling to assemble the C ring.
148. 148
  Mehta, G.; Singh, S. R. Total Synthesis of (±)-Merrilactone A Angew. Chem., Int. Ed. 2006, 45, 953– 955 DOI: 10.1002/anie.200503618
  148
  Total synthesis of (±)-merrilactone A
  Mehta, Goverdhan; Singh, S. Robindro
  Angewandte Chemie, International Edition (2006), 45 (6), 953-955CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A stereoselective total synthesis of the pentacyclic sesquiterpenoid (±)-merrilactone A (I) starting from 4,5-dimethyl-4-cyclopentene-1,3-dione was achieved. Merrilactone A has exhibited impressive neurotrophic activity (no biol. testing data presented), and it may be important for the development of therapeutic drugs for neurodegenerative disorders.
149. 149
  He, W.; Huang, J.; Sun, X.; Frontier, A. J. Total Synthesis of (±)-Merrilactone A via Catalytic Nazarov Cyclization J. Am. Chem. Soc. 2007, 129, 498– 499 DOI: 10.1021/ja068150i
  149
  Total Synthesis of (±)-Merrilactone A via Catalytic Nazarov Cyclization
  He, Wei; Huang, Jie; Sun, Xiufeng; Frontier, Alison J.
  Journal of the American Chemical Society (2007), 129 (3), 498-499CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The total synthesis of Merrilactone A (a neurotrophic agent) has been achieved. In the approach reported, simultaneous creation of the C-4 and C-5 stereocenters was accomplished stereospecifically using an unprecedented variant of the Nazarov cyclization. Addnl. studies focused upon this Lewis acid-catalyzed cyclization of a silyloxyfuran-contg. intermediate are presented.
150. 150
  Inoue, M.; Sato, T.; Hirama, M. Total Synthesis of (±)-Merrilactone A J. Am. Chem. Soc. 2003, 125, 10772– 10773 DOI: 10.1021/ja036587+
  There is no corresponding record for this reference.
151. 151
  Servrin, M.; Krief, A. Regioselective and [C,C] Connective Routes to Oxetane and Tetrahydrofuranes Tetrahedron Lett. 1980, 21, 585– 586 DOI: 10.1016/S0040-4039(01)85563-5
  There is no corresponding record for this reference.
152. 152
  Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. Reaction of Dimethyloxosulfonium Methylide with Epoxides. Preparation of Oxetanes J. Org. Chem. 1983, 48, 5133– 5134 DOI: 10.1021/jo00173a072
  152
  Reaction of dimethyloxosulfonium methylide with epoxides. Preparation of oxetanes
  Okuma, Kentaro; Tanaka, Yoshihiko; Kaji, Shinji; Ohta, Hiroshi
  Journal of Organic Chemistry (1983), 48 (25), 5133-4CODEN: JOCEAH; ISSN:0022-3263.
  Reaction of Me2S+(O)C-H2 with epoxides in Me3COH gave corresponding oxetanes I [R = H, Me, Ph; R1 = Ph, 4-ClC6H4, RR1 = (CH2)5] in 83-94% yields. Oxetanes were also synthesized in 80-97% yields by the reaction of 2-fold excess of Me2S+(O)C-H2 with RR1CO [R = H, Me, Et, Ph; R1 = Ph, 4-ClC6H4, 4-MeC6H4; RR1 = (CH2)5, MeCH(CH2CH2)2, Me2CCH(CH2CH2)2]. This is the first example of the double methylene transfer reaction of the ylide.
153. 153
  Welch, S. C.; Prakasa Rao, A. S. C. A Convenient One-Step Synthesis of 2,2-Disubstituted Oxetanes from Ketones J. Am. Chem. Soc. 1979, 101, 6135– 6136 DOI: 10.1021/ja00514a053
  153
  A convenient one-step synthesis of 2,2-disubstituted oxetanes from ketones
  Welch, Steven C.; Rao, A. S. C. Prakasa
  Journal of the American Chemical Society (1979), 101 (20), 6135-6CODEN: JACSAT; ISSN:0002-7863.
  A convenient and facile one-step synthesis of 2,2-disubstituted oxetanes from ketones utilizing the sodium anion of dimethyl-N-(p-toluenesulfonyl)sulfoximine in Me2SO is presented. Yields were 46-96%. Fifteen ketones, e.g., estrone 3-Me ether, camphor, 4-tert-butylcyclohexanone, 3-cholestanone, norcamphor, bicyclo[3.3.1]nonan-9-one, cyclohexanone and 2-tridecanone were converted to the corresponding oxetanes.
154. 154
  Welch, S. C.; Prakasa Rao, A. S. C.; Lyon, J. T.; Assercq, J. M. Synthesis of 2,2-Disubstituted Oxetanes from Ketones Wigh S-Methyl-S-(sodiomethyl)-N-(4-Tolylsulfonyl)sulfoximine J. Am. Chem. Soc. 1983, 105, 252– 257 DOI: 10.1021/ja00340a019
  There is no corresponding record for this reference.
155. 155
  Fitton, A. O.; Hill, J.; Jane, D. E.; Millar, R. Synthesis of Simple Oxetanes Carrying Reactive 2-Substituents Synthesis 1987, 1987, 1140– 1142 DOI: 10.1055/s-1987-28203
  There is no corresponding record for this reference.
156. 156
  Butova, E. D.; Barabash, A. V.; Petrova, A. A.; Kleiner, C. M.; Schreiner, P. R.; Fokin, A. A. Stereospecific Consecutive Epoxide Ring Expansion with Dimethylsulfoxonium Methylide J. Org. Chem. 2010, 75, 6229– 6235 DOI: 10.1021/jo101330p
  156
  Stereospecific Consecutive Epoxide Ring Expansion with Dimethylsulfoxonium Methylide
  Butova, Ekaterina D.; Barabash, Anastasiya V.; Petrova, Anna A.; Kleiner, Christian M.; Schreiner, Peter R.; Fokin, Andrey A.
  Journal of Organic Chemistry (2010), 75 (18), 6229-6235CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Consecutive ring-expansion reactions of oxiranes with dimethylsulfxonium methylide were studied exptl. and modeled computationally at the d. functional theory (DFT) and second-order Moller-Plesset (MP2) levels of theory utilizing a polarizable continuum model (PCM) to account for solvent effects. While the epoxide to oxetane ring expansion requires 13-17 kcal mol-1 activation and occurs at elevated temps., the barriers for the ring expansions to oxolanes are higher (ca. 25 kcal mol-1) and require heating to 125 °C. Further expansions of these oxolanes to the six-membered oxanes are hampered by high barriers (ca. 40 kcal mol-1). We obsd. the complete conservation of the enantiomeric purities for the nucleophilic ring expansions of enantiomeric 2-mono- and 2,2-disubstituted epoxides and oxetanes with dimethylsulfoxonium methylide. This is a convenient general approach for the high-yielding prepn. of optically active four- and five-membered cyclic ethers, e.g I and II, from oxiranes.
157. 157
  Fritz, S. P.; Moya, J. F.; Unthank, M. G.; McGarrigle, E. M.; Aggarwal, V. K. An Efficient Synthesis of Azetidines with (2-Bromoethyl)sulfonium Triflate Synthesis 2012, 44, 1584– 1590 DOI: 10.1055/s-0031-1290951
  157
  An efficient synthesis of azetidines with (2-bromoethyl)sulfonium triflate
  Fritz, Sven P.; Moya, Juan F.; Unthank, Matthew G.; McGarrigle, Eoghan M.; Aggarwal, Varinder K.
  Synthesis (2012), 44 (10), 1584-1590CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
  Easily accessible arylglycine derivs. were cyclized to azetidines by using com. available (2-bromoethyl)sulfonium triflate in a simple and mild procedure. The high-yielding reaction has a relatively broad scope and was extended to the synthesis of an oxetane.
158. 158
  Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Catalytic Asymmetric Synthesis of 2,2-Disubstituted Oxetanes From Ketones by Using a One-Pot Sequential Addition of Sulfur Ylide Angew. Chem., Int. Ed. 2009, 48, 1677– 1680 DOI: 10.1002/anie.200805473
  158
  Catalytic asymmetric synthesis of 2,2-disubstituted oxetanes from ketones by using a one-pot sequential addition of sulfur ylide
  Sone, Toshihiko; Lu, Gang; Matsunaga, Shigeki; Shibasaki, Masakatsu
  Angewandte Chemie, International Edition (2009), 48 (9), 1677-1680CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Enantiopure 2-Me-2-R-substituted oxetanes (R = n-octyl, 9-decenyl, cyclohexyl, Ph, 4-ClC6H4, 4-FC6H4, PhCH2CH2, 2-naphthyl) were synthesized from the corresponding ketones RCOMe and dimethyloxosulfonium methylide via one-pot double methylene transfer catalyzed by a heterobimetallic La/Li complex. Chiral amplification in the second step was the key to obtain oxetanes in high enantiomeric excess.
159. 159
  Hintzer, K.; Koppenhoefer, B.; Schurig, V. Access to (S)-2-Methyloxetane and the Precursor (S)-1,3-Butanediol of High Enantiomeric Purity J. Org. Chem. 1982, 47, 3850– 3854 DOI: 10.1021/jo00141a009
  There is no corresponding record for this reference.
160. 160
  Jenkinson, S. F.; Fleet, G. W. J. Oxetanes from the Ring Contraction of α-Triflates from γ-Lactones: Oxetane Nucleosides and Oxetane Amino Acids Chimia 2011, 65, 71– 75 DOI: 10.2533/chimia.2011.71
  160
  Oxetanes from the ring contraction of α-triflates of γ-lactones: oxetane nucleosides and oxetane amino acids
  Jenkinson, Sarah F.; Fleet, George W. J.
  Chimia (2011), 65 (1-2), 71-75CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
  A review with refs. α-Triflates of γ-lactones with potassium carbonate in methanol give efficient contraction of the ring to oxetane-1-carboxylates in which the oxygen substituent at C(3) of the oxetane is predominantly trans to the carboxylate at C(2), regardless of the stereochem. of the starting triflate. The limitations of the procedure are discussed and compared with analogous reactions for the prepn. of THF carboxylates. The potential of the contraction in the prepn. of oxetane nucleosides (such as oxetanocin) and oxetane sugar amino acids (analogs of oxetin) as peptidomimetics with pre-disposition to form secondary structural motifs is illustrated.
161. 161
  Austin, G. N.; Fleet, G. W. J.; Peach, J. M.; Prout, K.; Son, J. C. Chiral Oxetanes from Sugar Lactones: Synthesis of Derivatives of 3,5-Anhydro-1,2-O-Isopropylidine-α-D-Glucuronic Acid and of 3,5-Anhydro-1,2-O-Isopropylidine-β-L-Iduronic Acid Tetrahedron Lett. 1987, 28, 4741– 4744 DOI: 10.1016/S0040-4039(00)96614-0
  161
  Chiral oxetanes from sugar lactones: synthesis of derivatives of 3,5-anhydro-1,2-O-isopropylidene-α-D-glucuronic acid and of 3,5-anhydro-1,2-O-isopropylidene-β-L-iduronic acid
  Austin, G. N.; Fleet, G. W. J.; Peach, J. M.; Prout, K.; Son, Jong Chan
  Tetrahedron Letters (1987), 28 (40), 4741-4CODEN: TELEAY; ISSN:0040-4039.
  Ring contraction reactions of triflates of α-hydroxy-γ-lactones provide an approach to the synthesis of chiral polyfunctionalized oxetanes from sugars. Treatment of 1,2-O-isopropylidene-5-O-trifluoromethanesulfonyl-α-D-glucuronolactone (I) with benzylamine or with K2CO3 in MeOH gave ring contraction reactions to form oxetanes, e.g., II, in good yield.
162. 162
  Dax, K.; Weidmann, H. Reactions of D-Glucofuranurono-6,3-Lactone Adv. Carbohydr. Chem. Biochem. 1976, 33, 189– 234 DOI: 10.1016/S0065-2318(08)60282-6
  There is no corresponding record for this reference.
163. 163
  Bashyal, B. P.; Chow, H.-F.; Fellows, L. E.; Fleet, G. W. J. The Synthesis of Polyhydroxylated Amino Acids from Glucuronolactone: Enantiospecific Syntheses of 2S, 3R, 4R, 5S-Trihydroxypipecolic Acid, 2R, 3R, 4R, 5S-Trihydroxypipecolic Acid and 2R, 3R, 4R-Dihydroxyproline Tetrahedron 1987, 43, 415– 422 DOI: 10.1016/S0040-4020(01)89972-5
  There is no corresponding record for this reference.
164. 164
  Csuk, R.; Honig, H.; Nimp, J.; Weidmann, H. A Facile Synthesis of 1,2,-O-Isopropylidene-B-L-Idofuranurono-6,3-Lactone Tetrahedron Lett. 1980, 21, 2135– 2136 DOI: 10.1016/S0040-4039(00)78978-7
  There is no corresponding record for this reference.
165. 165
  Barton, D. H. R.; Crich, D.; Motherwell, W. B. The Invention Of New Radical Chain Reactions. Part VIII. Radical Chemistry Of Thiohydroxamic Esters; A New Method For The Generation Of Carbon Radicals From Carboxylic Acids Tetrahedron 1985, 41, 3901– 3924 DOI: 10.1016/S0040-4020(01)97173-X
  165
  The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters; a new method for the generation of carbon radicals from carboxylic acids
  Barton, Derek H. R.; Crich, David; Motherwell, William B.
  Tetrahedron (1985), 41 (19), 3901-24CODEN: TETRAB; ISSN:0040-4020.
  The aliph. and alicyclic esters of N-hydroxypyridine-2-thione were reduced by Bu3SnH in a radical chain reaction to furnish noralkanes. In the absence of the stannane, a smooth decarboxylative rearrangement occurred to give 2-substituted thiopyridines. Radical intermediates reacted with Me3CSH to form noralkane and 2-pyridyl tert-Bu disulfide. The carbon radicals were also captured by halogen atom transfer to give noralkyl chlorides, bromides, and iodides. In the presence of O and Me3CSH, the corresponding noralkyl hydroperoxides were formed by another radical chain reaction.
166. 166
  Fleet, G. W. J.; Son, J. C.; Peach, J. M.; Hamor, T. A. Synthesis and X-Ray Crystal Structure of a Stable α-Chlorooxetane Tetrahedron Lett. 1988, 29, 1449– 1450 DOI: 10.1016/S0040-4039(00)80321-4
  There is no corresponding record for this reference.
167. 167
  Fleet, G. W. J.; Son, J. C.; Vogt, K.; Peach, J. M.; Hamor, T. A. Reaction of Adenine with an α-Chlorooxetane: An Approach to the Synthesis of Oxetane Nucleosides Tetrahedron Lett. 1988, 29, 1451– 1452 DOI: 10.1016/S0040-4039(00)80322-6
  There is no corresponding record for this reference.
168. 168
  Witty, D. R.; Fleet, G. W. J.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Ring Contraction of 2-O-Trifluoromethanesulphonates of α-Hydroxy-γ-Lactones to Oxetane Carboxylic Esters Tetrahedron Lett. 1990, 31, 4787– 4790 DOI: 10.1016/S0040-4039(00)97734-7
  There is no corresponding record for this reference.
169. 169
  Witty, D. R.; Fleet, G. W. J.; Choi, S.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Ring Contraction of 3-Deoxy-2-O-trifluoromethanesulphonates of α-Hydroxy-γ-Lactones to Oxetanes Tetrahedron Lett. 1990, 31, 6927– 6930 DOI: 10.1016/S0040-4039(00)97209-5
  169
  Ring contraction of 3-deoxy-2-O-trifluoromethanesulfonates of α-hydroxy-γ-lactones to oxetanes
  Witty, D. R.; Fleet, G. W. J.; Choi, S.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J.
  Tetrahedron Letters (1990), 31 (47), 6927-30CODEN: TELEAY; ISSN:0040-4039.
  α-Triflates of 3-deoxy-1,4-lactones bearing H or alkyl substituents in the 3-position undergo ring contraction to Me oxetane-2-carboxylates on treatment with K2CO3-MeOH.
170. 170
  Wilson, F. X.; Fleet, G. W. J.; Vogt, K.; Wang, Y.; Witty, D. R.; Choi, S.; Storer, R.; Myers, P. L.; Wallis, C. J. Synthesis of Oxetanocin Tetrahedron Lett. 1990, 31, 6931– 6934 DOI: 10.1016/S0040-4039(00)97210-1
  170
  Synthesis of oxetanocin
  Wilson, F. X.; Fleet, G. W. J.; Vogt, K.; Wang, Y.; Witty, D. R.; Choi, S.; Storer, R.; Myers, P. L.; Wallis, C. J.
  Tetrahedron Letters (1990), 31 (47), 6931-4CODEN: TELEAY; ISSN:0040-4039.
  Oxetanocin (I) and its α-epimer were prepd. by reaction of adenine with a protected 3-hydroxymethyl-2-chlorooxetane. Attempts to synthesize C-2' alkyl analogs of oxetanocin by analogous reactions indicate the limitation of this strategy for the synthesis of oxetane nucleosides. I had a virucidal ED50 against HIV of 0.5-1.5 μg/mL whereas its epimer was inactive.
171. 171
  Wilson, F. X.; Fleet, G. W. J.; Witty, D. R.; Vogt, K.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Synthesis of the Oxetane Nucleosides α- and β-Noroxetanocin Tetrahedron: Asymmetry 1990, 1, 525– 526 DOI: 10.1016/S0957-4166(00)80540-6
  There is no corresponding record for this reference.
172. 172
  Wang, Y.; Fleet, G. W. J.; Storer, R.; Myers, P. L.; Wallis, C. J.; Doherty, O.; Watkin, D. J.; Vogt, K.; Witty, D. R.; Wilson, F. X.; Peach, J. M. Synthesis of the Potent Antiviral Oxetane Nucleoside Epinooxetanocin from D-Lyxonolactone Tetrahedron: Asymmetry 1990, 1, 527– 530 DOI: 10.1016/S0957-4166(00)80541-8
  There is no corresponding record for this reference.
173. 173
  Saksena, A. K.; Ganguly, A. K.; Girijavallabhan, V. M.; Pike, R. E.; Chen, Y.-T.; Puar, M. S. Ring Contraction Reactions of 2-O-Methanesulfonates of α-Hydroxy-γ-Lactones in Aqueous Medium to Oxetane-2-Carboxylic Acids: A Convenient Synthesis of 3′-O-Methyloxetanocin and a Formal Synthesis of Oxetanocin Tetrahedron Lett. 1992, 33, 7721– 7724 DOI: 10.1016/0040-4039(93)88027-G
  There is no corresponding record for this reference.
174. 174
  Gumina, G.; Chu, C. K. Synthesis of L-Oxetanocin Org. Lett. 2002, 4, 1147– 1149 DOI: 10.1021/ol025562x
  174
  Synthesis of L-Oxetanocin
  Gumina, Giuseppe; Chu, Chung K.
  Organic Letters (2002), 4 (7), 1147-1149CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  Hitherto unknown L-oxetanocin has been synthesized from L-xylose in 16 steps via a ribonolactone deriv. L-Oxetanocin showed no activity up to 100 mM against HIV-1.
175. 175
  Wang, Y.; Fleet, G. W. J.; Wilson, F. X.; Storer, R.; Wallis, C. J.; Doherty, O.; Watkin, D. J.; Vogt, K.; Witty, D. R.; Peach, J. M. Oxetane Nucleosides with Fluorine and Azide Substituents: Nucleophilic Displacements on an Oxetane Ring Tetrahedron Lett. 1991, 32, 1675– 1678 DOI: 10.1016/S0040-4039(00)74302-4
  There is no corresponding record for this reference.
176. 176
  Johnson, S. W.; Angus, D.; Taillefumier, C.; Jones, J. H.; Watkin, D. J.; Floyd, E.; Buchanan, J. G.; Fleet, G. W. J. Two Epimerisations In The Formation Of Oxetanes From L-Rhamnose: Towards Oxetane-Containing Peptidomimetics Tetrahedron: Asymmetry 2000, 11, 4113– 4125 DOI: 10.1016/S0957-4166(00)00360-8
  There is no corresponding record for this reference.
177. 177
  Barker, S. F.; Angus, D.; Taillefumier, C.; Probert, M. R.; Watkin, D. J.; Watterson, M. P.; Claridge, T. D. W.; Hungerford, N. L.; Fleet, G. W. J. cis- and trans-3-Azido-Oxetane-2-Carboxylate Scaffolds: Hexamers Of Oxetane cis-B-Amino Acids Tetrahedron Lett. 2001, 42, 4247– 4250 DOI: 10.1016/S0040-4039(01)00660-8
  There is no corresponding record for this reference.
178. 178
  Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Jones, J. H.; Fleet, G. W. J.; Taillefumier, C. Oxetane Cis- and Trans-β-Amino-Acid Scaffolds from L-Rhamnose by Efficient SN2 Reactions in Oxetane Rings; Pseudoenantiomeric Analogues of the Antibiotic Oxetin Tetrahedron: Asymmetry 2004, 15, 2681– 2686 DOI: 10.1016/j.tetasy.2004.07.032
  There is no corresponding record for this reference.
179. 179
  Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Pérez-Victoria, I.; Claridge, T. D. W.; Fleet, G. W. J.; Jones, J. H. The Synthesis of Oligomers of Oxetane-Based Dipeptide Isosteres Derived from L-Rhamnose or D-Xylose J. Pept. Sci. 2005, 11, 303– 318 DOI: 10.1002/psc.622
  179
  The synthesis of oligomers of oxetane-based dipeptide isosteres derived from L-rhamnose or D-xylose
  Johnson, Stephen W.; Jenkinson, Sarah F.; Angus, Donald; Perez-Victoria, Ignacio; Claridge, Timothy D. W.; Fleet, George W. J.; Jones, John H.
  Journal of Peptide Science (2005), 11 (6), 303-318CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
  Routes to oligomers (dimers, tetramers, hexamers) of five oxetane-based dipeptide isosteres have been established. Me 2,4-anhydro-5-azido-5-deoxy-L-rhamnonate 'monomer' led, by coupling the corresponding carboxylic acid and amine, to a 'dimer'. Reverse-aldol ring-opening occurred on attempted sapon. of the dimer, so all further oligomerization was performed using TBDMS C-3 hydroxyl protection. The silyl protected L-rhamnonate monomer led in turn to the dimer (via the monomer acid and amine), the tetramer (via the dimer acid and amine) and finally the hexamer (via the tetramer acid and dimer amine). In each case the acids were obtained through sapon. of the resp. Me esters and the amines were obtained by hydrogenation of the azides; coupling was TBTU-mediated. Essentially the same strategy was employed on equiv. D-lyxonate, 6-deoxy-L-altronate, 6-deoxy-D-gulonate and D-fuconate dipeptide isosteres to give the resp. dimers, tetramers and hexamers.
180. 180
  Sakya, S. M.; Strohmeyer, T. W.; Bitha, P.; Lang, S. A., Jr.; Lin, Y.-I. Synthesis and Structure-Activity Relationships of Some Novel Oxetane Carbapenems Bioorg. Med. Chem. Lett. 1997, 7, 1805– 1810 DOI: 10.1016/S0960-894X(97)00280-1
  There is no corresponding record for this reference.
181. 181
  Leanza, W. J.; Wildonger, K. J.; Miller, T. W.; Christensen, B. G. N-Acetimidoyl- and N-Formimidoylthienamycin Derivatives: Antipseudomonal β-Lactam Antibiotics J. Med. Chem. 1979, 22, 1435– 1436 DOI: 10.1021/jm00198a001
  There is no corresponding record for this reference.
182. 182
  Johnson, S. W.; Jenkinson (née Barker), S. F.; Angus, D.; Jones, J. H.; Watkin, D. J.; Fleet, G. W. J. Pseudoenantiomeric Oxetane δ-Amino Acid Scaffolds Derived from L-Rhamnose and D-Xylose: D/L-Alanine-D-Serine and Glycine-L-Serine Dipeptide Isosteres Tetrahedron: Asymmetry 2004, 15, 3263– 3273 DOI: 10.1016/j.tetasy.2004.08.023
  There is no corresponding record for this reference.
183. 183
  Jenkinson (née Barker), S. F.; Harris, T.; Fleet, G. W. J. Oxetane cis- and trans β-Amino-Acid Scaffolds from D-Xylose by Efficient S_N2 Reactions in Oxetane Rings: Methyl and Hydroxymethyl Analogues of the Antibiotic Oxetin, an Oxetane β-Amino-Acid Tetrahedron: Asymmetry 2004, 15, 2667– 2679 DOI: 10.1016/j.tetasy.2004.07.031
  There is no corresponding record for this reference.
184. 184
  Knijnenburg, A. D.; Tuin, A. W.; Spalburg, E.; de Neeling, A. J.; Mars-Groenendijk, R. H.; Noort, D.; Otero, J. M.; Llamas-Saiz, A. L.; van Raaij, M. J.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. Exploring the Conformational and Biological Versatility of β-Turn-Modified Gramicidin S by Using Sugar Amino Acid Homologues That Vary in Ring Size Chem. - Eur. J. 2011, 17, 3995– 4004 DOI: 10.1002/chem.201002895
  184
  Exploring the conformational and biological versatility of β-turn-modified gramicidin S by using sugar amino acid homologs that vary in ring size
  Knijnenburg, Annemiek D.; Tuin, Adriaan W.; Spalburg, Emile; de Neeling, Albert J.; Mars-Groenendijk, Roos H.; Noort, Daan; Otero, Jose M.; Llamas-Saiz, Antonio L.; van Raaij, Mark J.; van der Marel, Gijs A.; Overkleeft, Herman S.; Overhand, Mark
  Chemistry - A European Journal (2011), 17 (14), 3995-4004, S3995/1-S3995/11CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (contg. an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties dets. the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-contg. peptides is solvent dependent. The deriv. contg. the pyranoid SAA is slightly less hydrophobic and displays a diminished hemolytic activity, but has similar antimicrobial properties as GS.
185. 185
  Claridge, T. D. W.; Lopez-Ortega, B.; Jenkinson, S. F.; Fleet, G. W. J. Secondary Structural Investigations into Homo-Oligomers of δ-2,4-Cis Oxetane Amino Acids Tetrahedron: Asymmetry 2008, 19, 984– 988 DOI: 10.1016/j.tetasy.2008.03.029
  There is no corresponding record for this reference.
186. 186
  Lopez-Ortega, B.; Jenkinson, S. F.; Claridge, T. D. W.; Fleet, G. W. J. Oxetane Amino Acids: Synthesis of Tetrameric and Hexameric Carbopeptoids Derived from L-Ribo 4-(aminomethyl)-Oxetan-2-Carboxylic Acid Tetrahedron: Asymmetry 2008, 19, 976– 983 DOI: 10.1016/j.tetasy.2008.03.030
  There is no corresponding record for this reference.
187. 187
  Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus, D.; Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet, G. W. J. 10-Helical Conformations In Oxetane B-Amino Acid Hexamers Tetrahedron Lett. 2001, 42, 4251– 4255 DOI: 10.1016/S0040-4039(01)00661-X
  There is no corresponding record for this reference.
188. 188
  Johnson, S. W.; Jenkinson (née Barker), S. F.; Pérez-Victoria, I.; Edwards, A. A.; Claridge, T. D. W.; Tranter, G. E.; Fleet, G. W. J.; Jones, J. H. Conformational Studies of Oligomeric Oxetane-Based Dipeptide Isosteres Derived From L-Rhamnose or D-Xylose J. Pept. Sci. 2005, 11, 517– 524 DOI: 10.1002/psc.658
  188
  Conformational studies of oligomeric oxetane-based dipeptide isosteres derived from L-rhamnose or D-xylose
  Johnson, Stephen W.; Jenkinson, Sarah F.; Perez-Victoria, Ignacio; Edwards, Alison A.; Claridge, Timothy D. W.; Tranter, George E.; Fleet, George W. J.; Jones, John H.
  Journal of Peptide Science (2005), 11 (9), 517-524CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
  Conformational investigations have been undertaken on oligomers (dimers, tetramers, hexamers) of five closely related oxetane-based dipeptide isosteres. All the oligomers were subjected to a range of studies by NMR, FT-IR and CD spectroscopy. The oligomers derived from Me 2,4-anhydro-5-azido-3-O-tert-butyldimethylsilyl-5-deoxy-L-rhamnonate "monomer" all exhibited evidence of ordered conformations in chloroform and 2,2,2-trifluoroethanol (TFE) soln. 5-Acetamido and N-methylamide derivs. of the L-rhamnonate "monomer", along with a "dimer" lacking silyl protection at C-3, were synthesized to ascertain the role of intramol. interactions. This led to the conclusion that, for the L-rhamnonate oligomers, steric interactions govern the conformational preference obsd. The equivalent silyl-protected D-lyxonate oligomers gave ordered CD spectra in TFE soln., but NMR and FT-IR spectroscopy in chloroform soln. suggested an irregular, non-hydrogen bonded system. The remaining silyl-protected 6-deoxy-L-altronate, 6-deoxy-D-gulonate and D-fuconate oligomers appear to be characterized by their lack of ordered conformation in TFE and chloroform soln.
189. 189
  Fleet, G. W. J.; Johnson, S. W.; Jones, J. H. Cyclic Oligomers of Oxetane-Based Dipeptide Isosteres Derived from L-Rhamnose J. Pept. Sci. 2006, 12 (8) 559– 561 DOI: 10.1002/psc.759
  189
  Cyclic oligomers of oxetane-based dipeptide isosteres derived from L-rhamnose
  Fleet, George W. J.; Johnson, Stephen W.; Jones, John H.
  Journal of Peptide Science (2006), 12 (8), 559-561CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
  Two new cyclic oligomers, cyclo-tetra-[2,4-anhydro-3-O-tert-butyldimethylsilyl-5-deoxy-L-rhamnonamido-(N→5)] and the corresponding 6-deoxy-D-gulonate cyclic 'tetramer', have been synthesized from linear tetrameric oligomers, using TBTU- and pentafluorophenyl ester-based methodologies, resp. These two compds. constitute a novel class of cyclic oligomers derived from oxetane-based sugar amino acids.
190. 190
  Sharma, G. V. M; Venkateshwarlu, G.; Katukuri, S.; Ramakrishna, K. V. S.; Sarma, A. V. S. Design and Synthesis of Novel Oxetane β³-Amino Acids and α,β-Peptides Tetrahedron 2015, 71, 2158– 2167 DOI: 10.1016/j.tet.2015.02.039
  There is no corresponding record for this reference.
191. 191
  Chan, L. C.; Cox, B. G. Kinetics of Amide Formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) Couplings J. Org. Chem. 2007, 72, 8863– 8869 DOI: 10.1021/jo701558y
  191
  Kinetics of Amide Formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) Couplings
  Chan, Lai C.; Cox, Brian G.
  Journal of Organic Chemistry (2007), 72 (23), 8863-8869CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the iso-Pr ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concn. of HOBt, showing that the rate-detg. step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the obsd. rate consts. for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH22+, 6) and the carboxylate group. The obsd. rate consts. fall sharply at high pH, as the fraction of EDCI as EDCIH22+ continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate const., kP, for reaction between the carboxylate group of acid, 3, and EDCIH22+ has a value of kP = 4.1 × 104 M-1 s-1 at 20 °C, some 105 times higher than similar rate consts. measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, dets. the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal arom. amine of 3 to give the diamide 5.
192. 192
  Pastor-Anglada, M.; Felipe, A.; Casado, F. J. Transport and Mode of Action of Nucleoside Derivatives Used in Chemical and Antiviral Therapies Trends Pharmacol. Sci. 1998, 19, 424– 430 DOI: 10.1016/S0165-6147(98)01253-X
  192
  Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies
  Pastor-Anglada, Marcal; Felipe, Antonio; Casado, F. Javier
  Trends in Pharmacological Sciences (1998), 19 (10), 424-430CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Science Ltd.)
  A review with 50 refs. Nucleoside analogs used in cancer and anti-viral therapies interfere with nucleotide metab. and DNA replication, thus inducing their pharmacol. effects. A long-awaited goal in the understanding of the pharmacol. properties of these mols., that is the mol. characterization of nucleoside plasma-membrane transporters, has been achieved very recently. These carrier proteins are encoded by at least two gene families and new isoforms remain to be identified. Direct demonstration of translocation of these drugs by nucleoside transporters has already been provided and most of them can inhibit natural nucleoside-transport, probably in a competitive manner. The expression of these genes is clearly tissue-specific and might depend on the differentiated status of a cell. This is relevant because the sensitivity of a cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might modulate nucleoside carrier expression. In this article, Marcal Pastor-Anglada, Antonio Felipe and Javier Casado discuss recent studies on the regulation of nucleoside carrier expression and of the mol. determinants of substrate specificity. Better knowledge of these will contribute to an improved design of therapies based on nucleoside derivs.
193. 193
  Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Nucleoside Analogues and Nucleobases in Cancer Treatment Lancet Oncol. 2002, 3, 415– 424 DOI: 10.1016/S1470-2045(02)00788-X
  193
  Nucleoside analogues and nucleobases in cancer treatment
  Galmarini, Carlos M.; Mackey, John R.; Dumontet, Charles
  Lancet Oncology (2002), 3 (7), 415-424CODEN: LOANBN; ISSN:1470-2045. (Lancet Publishing Group)
  A review. Cytotoxic nucleoside analogs and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. This family of compds. has grown to include a variety of purine and pyrimidine nucleoside derivs. with activity in both solid tumors and malignant disorders of the blood. These agents behave as antimetabolites, compete with physiol. nucleosides, and interact with a large no. of intracellular targets to induce cytotoxicity. Progress has recently been made in the identification and characterization of nucleoside transporters and the enzymes of nucleoside metab. In addn., there is now greater understanding of the mol. mechanisms of anticancer nucleoside activity, which provides opportunities for potentiating their antitumor effects. Strategies to optimize intracellular analog accumulation and to enhance cancer-cell selectivity are proving beneficial in clin. trials.
194. 194
  Prusoff, W. H. Synthesis and Biological Activities of Iododeoxyuridine, An Analogue Of Thymidine Biochim. Biophys. Acta 1959, 32, 295– 296 DOI: 10.1016/0006-3002(59)90597-9
  There is no corresponding record for this reference.
195. 195
  Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St Clair, M. H.; Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder, S. 3′-Azido-3′-deoxythymidine (BW A509U): An Antiviral Agent That Inhibits The Infectivity And Cytopathic Effect Of Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus In Vitro Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 7096– 7100 DOI: 10.1073/pnas.82.20.7096
  195
  3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro
  Mitsuya, Hiroaki; Weinhold, Kent J.; Furman, Phillip A.; St. Clair, Marty H.; Lehrman, Sandra Nusinoff; Gallo, Robert C.; Bolognesi, Dani; Barry, David W.; Broder, Samuel
  Proceedings of the National Academy of Sciences of the United States of America (1985), 82 (20), 7096-100CODEN: PNASA6; ISSN:0027-8424.
  The antiviral effects of a thymidine analog, 3'-azido-3'-deoxythymidine (BW A509U)(I) [30516-87-1], which, as a triphosphate, inhibits the reverse transcriptase of human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-assocd. virus (LAV) was detd. This agent blocked the expression of the p24 gag protein of HTLV-III/LAV in H9 cells following exposure to virus. The drug also inhibited the cytopathic effect of HTLV-IIIB (a virus derived from a pool of American patients) and HTLV-III/RF-II (an isolate obtained from a Haitian patient that differs by about 20% in the amino acid sequence of the envelope gene from several isolates of HTLV-III/LAV, including HTLV-IIIB, analyzed so far). 3'-Azido-3'-deoxythymidine also completely blocked viral replication as assessed by reverse transcriptase prodn. in normal human peripheral blood mononuclear cells exposed to HTLV-III. Finally, at concns. of 3'-azido-3'-deoxythymidine that block the in vitro infectively and cytopathic effect of HTLV-IIIB, the in vitro immune functions of normal T cells remain basically intact. These results are relevant to the treatment of AIDS.
196. 196
  Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.; Zahler, R.; Colonno, R. J. Identification of BMS-200475 as a Potent and Selective Inhibitor of Hepatitus B Virus Antimicrob. Agents Chemother. 1997, 41, 1444– 1448
  There is no corresponding record for this reference.
197. 197
  Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Steuer, H. M. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus J. Med. Chem. 2010, 53, 7202– 7218 DOI: 10.1021/jm100863x
  197
  Discovery of a β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus
  Sofia, Michael J.; Bao, Donghui; Chang, Wonsuk; Du, Jinfa; Nagarathnam, Dhanapalan; Rachakonda, Suguna; Reddy, P. Ganapati; Ross, Bruce S.; Wang, Peiyuan; Zhang, Hai-Ren; Bansal, Shalini; Espiritu, Christine; Keilman, Meg; Lam, Angela M.; Steuer, Holly M. Micolochick; Niu, Congrong; Otto, Michael J.; Furman, Phillip A.
  Journal of Medicinal Chemistry (2010), 53 (19), 7202-7218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-Me nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate deriv. of the β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepd. and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixt. 14 was crystd., and an X-ray structure was detd. establishing the phosphoramidate stereochem. as Sp, thus correlating for the first time the stereochem. of a phosphoramidate prodrug with biol. activity. 51 (PSI-7977) was selected as a clin. development candidate.
198. 198
  De Clercq, E. De. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies For Intervention With HIV Infections J. Med. Chem. 1995, 38, 2491– 2517 DOI: 10.1021/jm00014a001
  198
  Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections
  De Clercq, Erik
  Journal of Medicinal Chemistry (1995), 38 (14), 2491-517CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review, with 250 refs.
199. 199
  Gish, R. G.; Clark, M. D.; Kane, S. D.; Shaw, R. E.; Mangahas, M. F.; Baqai, S. Similar Risk of Renal Events Among Patients Treated With Tenofovir or Entecavir for Chronic Hepatitis B Clin. Gastroenterol. Hepatol. 2012, 10, 941– 946 DOI: 10.1016/j.cgh.2012.04.008
  199
  Similar risk of renal events among patients treated with tenofovir or entecavir for chronic hepatitis B
  Gish Robert G; Clark Margaret D; Kane Steve D; Shaw Richard E; Mangahas Michael F; Baqai Sumbella
  Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2012), 10 (8), 941-6; quiz e68 ISSN:.
  BACKGROUND & AIMS: Tenofovir is a nucleotide reverse-transcriptase inhibitor approved for treatment of human immunodeficiency virus infection, as well as chronic hepatitis B (CHB). We evaluated nephrotoxicity among patients with CHB treated with tenofovir. METHODS: We performed a community-based, retrospective cohort study of 80 patients with CHB who received tenofovir, alone or in a combination regimen; they were matched for age and sex with 80 CHB patients who received only entecavir. Incidences of serum creatinine (SCr) increase ≥0.2 mg/dL and new SCr levels of 1.5, 2.0, or 2.5 mg/dL were assessed. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min, calculated using the Modification of Diet in Renal Disease or Cockcroft-Gault formula, or who had ≥20% decrease in eGFR were also recorded. RESULTS: More patients given entecavir had increases in SCr ≥2.5 mg/dL (1 vs 6; P = .053), whereas more patients given tenofovir had a new Cockcroft-Gault eGFR of <60 mL/min (15 vs 6; P = .022) and at least 1 dose adjustment (13 vs 4; P = .021). By multivariate analysis, the only significant factors associated with an increase in SCr were a history of organ transplantation (adjusted odds ratio, 6.740; 95% confidence interval, 1.799-28.250; P = .005) and pre-existing renal insufficiency (adjusted odds ratio, 10.960; 95% confidence interval, 2.419-48.850; P = .002). No factors, including therapy assignment, were associated with a new eGFR <60 mL/min. CONCLUSIONS: Markers of renal function indicated that patients who received tenofovir were no more likely to have changes in renal function than patients treated with entecavir. History of transplant and pre-existing renal insufficiency were the only factors independently associated with increases in SCr.
200. 200
  Chemical Synthesis of Nucleoside Analogues; Merino, P., Ed.; John Wiley & Sons: Hoboken, NJ, 2013; DOI: DOI: 10.1002/9781118498088 .
  There is no corresponding record for this reference.
201. 201
  Christensen, N. K.; Petersen, M.; Nielsen, P.; Jacobsen, J. P.; Olsen, C. E.; Wengel, J. A Novel Class of Oligonucleotide Analogues Containing 2′-O,3′-C-Linked [3.2.0]Bicycloarabinonucleoside Monomers: Synthesis, Thermal Affinity Studies, and Molecular Modeling J. Am. Chem. Soc. 1998, 120, 5458– 5463 DOI: 10.1021/ja9743598
  There is no corresponding record for this reference.
202. 202
  Sørensen, M. H.; Nielsen, C.; Nielsen, P. Synthesis of a Bicyclic Analogue of AZT Restricted in an Unusual O4′-Endo Conformation J. Org. Chem. 2001, 66, 4878– 4886 DOI: 10.1021/jo010299j
  There is no corresponding record for this reference.
203. 203
  Sharma, P. K.; Nielsen, P. New Ruthenium-Based Protocol for Cleavage of Terminal Olefins to Primary Alcohols: Improved Synthesis of a Bicyclic Nucleoside J. Org. Chem. 2004, 69, 5742– 5745 DOI: 10.1021/jo0491861
  There is no corresponding record for this reference.
204. 204
  Pradeepkumar, P. I.; Chattopadhyaya, J. Oxetane Modified Antisense Oligonucleotides Promote RNase H Cleavage of the Complementary RNA Strand in the Hybrid Duplex as Efficiently as the Native, and Offer Improved Endonuclease Resistance J. Chem. Soc. Perkin Trans. 2 2001, 2074– 2083 DOI: 10.1039/b106281f
  204
  Oxetane modified antisense oligonucleotides promote RNase H cleavage of the complementary RNA strand in the hybrid duplex as efficiently as the native, and offer improved endonuclease resistance
  Pradeepkumar, Pushpangadan I.; Chattopadhyaya, Jyoti
  Journal of the Chemical Society, Perkin Transactions 2 (2001), (11), 2074-2083CODEN: JCSPGI; ISSN:1472-779X. (Royal Society of Chemistry)
  Although the Tm drops ∼6/modification (note: Tm loss is ∼10/mismatch) in the oxetane, [1-(1',3'-O-anhydro-β-D-psicofuranosyl)thymine, T], modified antisense (AON)-RNA heteroduplexes, the relative rates of the complementary RNA cleavage by RNase H remain the same as or comparable to that of the native counterpart. The RNA cleavage in the native hybrid duplex was 68±3% (Tm = 44), whereas it was 64±10% for the single T modified AON-RNA duplex (Tm = 39), 56±9% for the double T modified AON-RNA duplex (Tm = 33) and 60±7% for the triple T modified AON-RNAs (Tm = 26). The oxetane modifications in AON reduce the endonuclease cleavage (DNase 1) significantly. One modification gives ∼2-fold protection and three modifications give ∼4-fold protection compared to that of the native. Introductions of both interior oxetane modifications in conjunction with the 3'-DPPZ (dipyridophenazine) group give the resulting AON-RNA hybrid an RNase H cleavage rate at least the same as that of the native counterpart, which, addnl., gives full stability against both exo- and endonucleases. The conformational transmission of the constrained 3'-endo sugar of the oxetane nucleotide in the AON strand is transmitted up to a stretch of five nucleotides in the heteroduplex as is evident by the RNase H resistance to the cleavage of the complementary RNA strand, thereby showing that this five-nucleotide region most probably takes up a local RNA-RNA type conformation. This is the first report of an antisense oligonucleotide construct which fulfills three important criteria simultaneously: (1) the modified AON promotes the complementary RNA cleavage by RNase H at an efficiency comparable to that of the native counterpart, (2) the modified AON has substantially more endonuclease stability than that of the native AON, and finally, (3) the DPPZ group at the 3'-end provides the expected exonuclease stability. This also shows that the Tm increase of the AON-RNA hybrid duplex is not mandatory for RNase H promoted destruction of the target RNA.
205. 205
  Pradeepkumar, P. I.; Amirkhanov, N. V.; Chattopadhyaya, J. Antisense Oligonuclotides with Oxetane-Constrained Cytidine Enhance Heteroduplex Stability, and Elicit Satisfactory Rnase H Response as well as Showing Improved Resistance to Both Exo and Endonucleases Org. Biomol. Chem. 2003, 1, 81– 92 DOI: 10.1039/b210163g
  There is no corresponding record for this reference.
206. 206
  Bogucka, M.; Nauš, P.; Pathmasiri, W.; Barman, J.; Chattopadhyaya, J. Facile Preparation of the Oxetane-Nucleosides Org. Biomol. Chem. 2005, 3, 4362– 4372 DOI: 10.1039/b511406c
  There is no corresponding record for this reference.
207. 207
  Komsta, Z.; Mayes, B.; Moussa, A.; Shelbourne, M.; Stewart, A.; Tyrrell, A. J.; Wallis, L. L.; Weymouth-Wilson, A. C.; Yurek-George, A. Synthesis and Anti-HCV Activity of 1-(1′,3′-O-Anhydro-3′-C-methyl-β-D-psicofuranosyl)uracil Tetrahedron Lett. 2014, 55, 6216– 6219 DOI: 10.1016/j.tetlet.2014.09.069
  There is no corresponding record for this reference.
208. 208
  Chang, W.; Du, J.; Rachakonda, S.; Ross, B. S.; Convers-Reignier, S.; Yau, W. T.; Pons, J.-F.; Murakami, E.; Bao, H.; Steuer, H. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Synthesis and Anti-HCV Activity of 3′,4′-Oxetane Nucleosides Bioorg. Med. Chem. Lett. 2010, 20, 4539– 4543 DOI: 10.1016/j.bmcl.2010.06.025
  208
  Synthesis and anti-HCV activity of 3',4'-oxetane nucleosides
  Chang, Wonsuk; Du, Jinfa; Rachakonda, Suguna; Ross, Bruce S.; Convers-Reignier, Serge; Yau, Wei T.; Pons, Jean-Francois; Murakami, Eisuke; Bao, Haiying; Steuer, Holly Micolochick; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.
  Bioorganic & Medicinal Chemistry Letters (2010), 20 (15), 4539-4543CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Hepatitis C virus afflicts approx. 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clin. trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepd. as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as detd. in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivs. were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
209. 209
  Du, J.; Chun, B.-K; Mosley, R. T.; Bansal, S.; Bao, H.; Espiritu, C.; Lam, A. M.; Murakami, E.; Niu, C.; Steuer, H. M. M.; Furman, P. A.; Sofia, M. J. Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design J. Med. Chem. 2014, 57, 1826– 1835 DOI: 10.1021/jm401224y
  There is no corresponding record for this reference.
210. 210
  Jonckers, T. H. M.; Vandyck, K.; Vandekerckhove, L.; Hu, L.; Tahri, A.; Van Hoof, S.; Lin, T.-I; Vijgen, L.; Berke, J. M.; Lachau-Durand, S.; Stoops, B.; Leclercq, L.; Fanning, G.; Samuelsson, B.; Nilsson, M.; Rosenquist, Å.; Simmen, K.; Raboisson, P. Nucleotide Prodrugs of 2′-Deoxy-2′-Spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase J. Med. Chem. 2014, 57, 1836– 1844 DOI: 10.1021/jm4015422
  210
  Nucleotide Prodrugs of 2'-Deoxy-2'-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
  Jonckers, Tim H. M.; Vandyck, Koen; Vandekerckhove, Leen; Hu, Lili; Tahri, Abdellah; Van Hoof, Steven; Lin, Tse-I.; Vijgen, Leen; Berke, Jan Martin; Lachau-Durand, Sophie; Stoops, Bart; Leclercq, Laurent; Fanning, Gregory; Samuelsson, Bertil; Nilsson, Magnus; Rosenquist, Asa; Simmen, Kenny; Raboisson, Pierre
  Journal of Medicinal Chemistry (2014), 57 (5), 1836-1844CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects assocd. with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was obsd. in both rat and human hepatocyte cultures. In addn., after oral dosing of several phosphoramidate derivs. of compd. 21 (I) to rats, substantial hepatic levels of the active triphosphate metabolite were found.
211. 211
  Sharma, V. K.; Kumar, M.; Sharma, D.; Olsen, C. E.; Prasad, A. K. Chemoenzymatic Synthesis of C-4′-Spiro-Oxetanoribonucleosides J. Org. Chem. 2014, 79, 8516– 8521 DOI: 10.1021/jo501655j
  There is no corresponding record for this reference.
212. 212
  Ehlinger, E.; Magnus, P. Silicon in Synthesis. 10. The (Trimethylsilyl)allyl Anion: A β-Acyl Anion Equivalent for the Conversion of Aldehydes and Ketones into γ-Lactones J. Am. Chem. Soc. 1980, 102, 5004– 5011 DOI: 10.1021/ja00535a600
  212
  Silicon in synthesis. 10. The (trimethylsilyl)allyl anion: a β-acyl anion equivalent for the conversion of aldehydes and ketones into γ-lactones
  Ehlinger, Ed; Magnus, Philip
  Journal of the American Chemical Society (1980), 102 (4), 5004-11CODEN: JACSAT; ISSN:0002-7863.
  The (trimethylsilyl)allyl anion reacted with a no. of ketones and aldehydes to give adducts RCR1(OH)CH2CH:CHSiMe3; the adducts were epoxidized to provide the corresponding epoxy silanes I. Treatment of the I with MeOH in the presence of boron trifluoride etherate gave lactol Me ethers II, and Jones oxidn. of the lactol ethers gave γ-lactones III.
213. 213
  Manabe, S.; Nishino, C. Stereochemistry of cis-Clerodane Diterpenes Tetrahedron 1986, 42, 3461– 3470 DOI: 10.1016/S0040-4020(01)87313-0
  213
  Stereochemistry of cis-clerodane diterpenes
  Manabe, Shunichi; Nishino, Chikao
  Tetrahedron (1986), 42 (13), 3461-70CODEN: TETRAB; ISSN:0040-4020.
  To piscicidal solidagolactones IV, V, VII and VIII isolated from Solidago altissima, a nonsteroidal conformation was assigned on the basis of chem. and physicochem. evidence. 13C NMR chem. shifts of Me groups proved useful for detg. stereochem. of the A/B ring junction in clerodanes. For clerodanes having an epoxide, 1H NMR data and the Tori equation were useful for assigning the epoxide configuration. Cremer's puckering parameters were used to express the conformation of the solidagolactones.
214. 214
  Paquette, L. A.; Edmondson, S. D.; Monck, N.; Rogers, R. D. Studies Directed toward the Synthesis of the Unusual Antileukemic Diterpene Jatrophatrione. 2. Functionalization of Advanced Polycyclic Precursors to the 9-Epi and 8,9-Dehydro Congeners J. Org. Chem. 1999, 64, 3255– 3265 DOI: 10.1021/jo982526w
  214
  Studies Directed toward the Synthesis of the Unusual Antileukemic Diterpene Jatrophatrione. 2. Functionalization of Advanced Polycyclic Precursors to the 9-Epi and 8,9-Dehydro Congeners
  Paquette, Leo A.; Edmondson, Scott D.; Monck, Nathaniel; Rogers, Robin D.
  Journal of Organic Chemistry (1999), 64 (9), 3255-3265CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The synthesis of highly functionalized [5.9.5]tricyclic systems closely related to jatrophatrione (I; R = α-H) and 9-epijatrophatrione (I; R = β-H) is described. The first set of expts. provides a route to the conjugated 7-methylene ketones II (R1 = C6H4OMe-4, H), both of which resist migration of the exocyclic double bond to a position internal to the ring. Subsequent dihydroxylation studies define a convenient pathway from III to triketone IV, which has yet to exhibit a tendency to undergo appropriate dehydration at the tertiary carbinol center. The presence of a carbonyl group in ring C was shown not to be contributory to this low reactivity. Finally, a protocol involving formation of a bromo oxetane with subsequent introduction of a C8-C9 double bond and Grob fragmentation has shown promise for arrival at I by making available the diene V.
215. 215
  Evans, R. D.; Magee, J. W.; Schauble, J. H. Halocyclization of Unsaturated Alcohols and Carboxylic Acids Using Bis(sym-collidine)iodine(I) Perchlorate Synthesis 1988, 1988, 862– 868 DOI: 10.1055/s-1988-27731
  There is no corresponding record for this reference.
216. 216
  Jung, M. E.; Nichols, C. J. Highly Stereoselective Synthesis of trans,trans-4-aryl-2,3-Oxetanedimethanols: Preparation of Oxetanocin A Analogues Tetrahedron Lett. 1996, 37, 7667– 7670 DOI: 10.1016/0040-4039(96)01720-0
  There is no corresponding record for this reference.
217. 217
  Galatsis, P.; Millan, S. D.; Ferguson, G. Enantioselective Construction of Cyclic Ethers by An Aldol-Cyclization Sequence J. Org. Chem. 1997, 62, 5048– 5056 DOI: 10.1021/jo961904z
  There is no corresponding record for this reference.
218. 218
  Galatsis, P.; Millan, S. D.; Nechala, P.; Ferguson, G. Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans J. Org. Chem. 1994, 59, 6643– 6651 DOI: 10.1021/jo00101a024
  218
  Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans
  Galatsis, Paul; Millan, Scott D.; Nechala, Patrik; Ferguson, George
  Journal of Organic Chemistry (1994), 59 (22), 6643-51CODEN: JOCEAH; ISSN:0022-3263.
  The application of a tandem deconjugative aldol-cyclization sequence for the construction of substituted tetrahydrofurans was examd. The aldol condensation of alkenoates proceeded with alkylation at the α-position to generate homoallylic alc. moieties. These compds. could be induced to cyclize under the influence of iodine via an endo mode. The stereoselectivity for the cyclization occurred in good to excellent fashion. X-ray crystal structure anal. of three of the tetrahydrofurans established unambiguously the product stereochem. This was used to propose a transition structure for the cyclization which correctly predicts the obsd. product stereochem. By this method, virtually all the possible stereoisomers for the substituted tetrahydrofurans can be constructed by judicious choice of aldol product and/or olefin geometry.
219. 219
  Rofoo, M.; Roux, M.-C.; Rousseau, G. Preparation of Oxetanes by Silicon-Directed 4-Exo Trig Electrophilic Cyclisations of Homoallylic Alcohols Tetrahedron Lett. 2001, 42, 2481– 2484 DOI: 10.1016/S0040-4039(01)00227-1
  There is no corresponding record for this reference.
220. 220
  Brown, W. L.; Fallis, A. G. Intramolecular Rearrangements: Epimerization of Bicyclic Vinyl Tertiary Alcohols via a [2,3] Sulfoxide Sigmatropic Rearrangement Can. J. Chem. 1987, 65, 1828– 1832 DOI: 10.1139/v87-307
  There is no corresponding record for this reference.
221. 221
  Arjona, O.; de la Pradilla, R. F.; Plumet, J.; Viso, A. Regioselective Electrophilic Additions to 2-Oxygenated-7-xabicyclo[2.2.1]hept-5-enes: A Simple Entry into the 4,7-Dioxatricyclo[3.2.1.0^3,6]octaneskeleton Tetrahedron 1989, 45, 4565– 4578 DOI: 10.1016/S0040-4020(01)89091-8
  There is no corresponding record for this reference.
222. 222
  Arjona, O.; de la Pradilla, R. F.; Plumet, J.; Viso, A. Temperature-Controlled Synthesis of 4,7-Dioxatricyclo[3.2.1.0^3,6]octane Derivatives J. Org. Chem. 1992, 57, 772– 774 DOI: 10.1021/jo00028a074
  There is no corresponding record for this reference.
223. 223
  Homsi, F.; Rousseau, G. 4-Endo-Trig Cyclization Processes Using Bis(collidine)bromine(I) Hexafluorophosphate as Reagent: Preparation of 2-Oxetanones, 2-Azetidinones, and Oxetanes J. Org. Chem. 1999, 64, 81– 85 DOI: 10.1021/jo9810361
  223
  4-Endo-Trig Cyclization Processes Using Bis(collidine)bromine(I) Hexafluorophosphate as Reagent: Preparation of 2-Oxetanones, 2-Azetidinones, and Oxetanes
  Homsi, Fadi; Rousseau, Gerard
  Journal of Organic Chemistry (1999), 64 (1), 81-85CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Reaction in methylene chloride of bis(collidine)bromine hexafluorophosphate with α,β-unsatd. acids and α,β-unsatd. N-sulfonamides was found to lead diastereospecifically to the corresponding 2-oxetanones and 2-azetidinones in moderate yields (23-60%), by an almost unknown 4-endo cyclization. This process allow the synthesis of these interesting classes of products in one step from common substrates. Similarly, the reaction of cinnamic alcs. led, by the same cyclization procedure, to oxetanes (20-36%); the presence of a gem-di-Me group in α of the alc. function appeared beneficial.
224. 224
  Albert, S.; Robin, S.; Rousseau, G. Preparation of Oxetanes by 4-Endo Trig Electrophilic Cyclisations of Cinnamic Alcohols Tetrahedron Lett. 2001, 42, 2477– 2479 DOI: 10.1016/S0040-4039(01)00226-X
  There is no corresponding record for this reference.
225. 225
  Willand-Charnley, R.; Puffer, B. W.; Dussault, P. H. Oxacycle Synthesis via Intramolecular Reaction of Carbanions and Peroxides J. Am. Chem. Soc. 2014, 136, 5821– 5823 DOI: 10.1021/ja5026276
  225
  Oxacycle Synthesis via Intramolecular Reaction of Carbanions and Peroxides
  Willand-Charnley, Rachel; Puffer, Benjamin W.; Dussault, Patrick H.
  Journal of the American Chemical Society (2014), 136 (16), 5821-5823CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The intramol. reaction of dialkyl peroxides with carbanions, generated via chemoselective metal-heteroatom exchange or deprotonation, provides a new approach to cyclic ethers. Applied in tandem with C-C bond formation, the strategy enables a one-step annelation to form spirocyclic oxacycles. E.g., in presence of KOCMe3 in THF, PhCO(CH2)4OOCMe3 underwent cyclization to give 81% THF deriv. (I).
226. 226
  Thijs, L.; Cillissen, P. J. M.; Zwanenburg, B. An Efficient Synthesis of Oxetanones from α,β-Epoxy Diazomethyl Ketones Tetrahedron 1992, 48, 9985– 9990 DOI: 10.1016/S0040-4020(01)92288-4
  There is no corresponding record for this reference.
227. 227
  Ye, L.; He, W.; Zhang, L. Gold-Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from Readily Available Propargylic Alcohols J. Am. Chem. Soc. 2010, 132, 8550– 8551 DOI: 10.1021/ja1033952
  227
  Gold-Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from Readily Available Propargylic Alcohols
  Ye, Longwu; He, Weimin; Zhang, Liming
  Journal of the American Chemical Society (2010), 132 (25), 8550-8551CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A general soln. for the synthesis of various oxetan-3-ones, e.g. I, has been developed. This reaction uses readily available propargylic alcs. as substrates and proceeds without the exclusion of moisture or air ("open flask"). Notably, oxetan-3-one, a highly valuable substrate for drug discovery, can be prepd. in one step from propargyl alc. in a fairly good yield. The facile formation of the strained oxetane ring provides strong support for the intermediacy of α-oxo gold carbenes. This safe and efficient generation of gold carbenes via intermol. alkyne oxidn. offers a potentially general entry into α-oxo metal carbene chem. without using hazardous diazo ketones.
228. 228
  Sharma, R.; Williams, L. J. Oxetan-3-ones from Allenes via Spirodiepoxides Org. Lett. 2013, 15, 2202– 2205 DOI: 10.1021/ol400749e
  There is no corresponding record for this reference.
229. 229
  Craig, D.; Munasinghe, V. R. N. Stereoselective Template-Directed C-Glycosidation. Synthesis of Bicyclic Ketooxetanes via Intramolecular Cyclization Reactions of (2-Pyridylthio)Glycosidic Silyl Enol Ethers J. Chem. Soc., Chem. Commun. 1993, 901– 903 DOI: 10.1039/c39930000901
  There is no corresponding record for this reference.
230. 230
  Craig, D.; Munasinghe, V. R. N.; Tierney, J. P.; White, A. J. P.; Williams, D. J.; Williamson, C. Template-Directed Intramolecular C-Glycosidation. Cation-Mediated Synthesis of Ketooxetanes from Thioglycosides Tetrahedron 1999, 55, 15025– 15044 DOI: 10.1016/S0040-4020(99)00959-X
  There is no corresponding record for this reference.
231. 231
  Craig, D.; Tierney, J. P.; Williamson, C. Template-Directed Intramolecular C-Glycosidation. Stereoselective Synthesis of Bicyclic Ketooxetanes from Anomeric Sulfones Tetrahedron Lett. 1997, 38, 4153– 4156 DOI: 10.1016/S0040-4039(97)00808-3
  There is no corresponding record for this reference.
232. 232
  Craig, D.; Lawrence, R. M.; Tapolczay, D. J. Stereoselective Synthesis of a Bicyclic Ketooxetane via a Thionium Ion-Mediated Cyclisation Reaction Synlett 1997, 1997, 1001– 1003 DOI: 10.1055/s-1997-949
  There is no corresponding record for this reference.
233. 233
  Still, W. C. Allyloxycarbanions, Cyclizations to Vinyl Oxetanes Tetrahedron Lett. 1976, 17, 2115– 2118 DOI: 10.1016/S0040-4039(00)93133-2
  There is no corresponding record for this reference.
234. 234
  Bird, C. W.; Hormozi, N. The Scope of a New Approach to Tetrahydrooxepanol Synthesis Tetrahedron Lett. 1990, 31, 3501– 3504 DOI: 10.1016/S0040-4039(00)97434-3
  There is no corresponding record for this reference.
235. 235
  Williams, D. R.; Grote, J. Ring Formation by Base-Dependent Isomerizations of Epoxybenzyl Ethers J. Org. Chem. 1983, 48, 134– 136 DOI: 10.1021/jo00149a031
  There is no corresponding record for this reference.
236. 236
  Mordini, A.; Bindi, S.; Pecchi, S.; Degl’Innocenti, A.; Reginato, G.; Serci, A. Different Pathways in the Base-Promoted Isomerization of Benzyl Oxiranyl Ethers J. Org. Chem. 1996, 61, 4374– 4378 DOI: 10.1021/jo960226d
  There is no corresponding record for this reference.
237. 237
  Thurner, A.; Faigl, F.; Mordini, A.; Bigi, A.; Reginato, G.; Töke, L. A New Base Promoted Rearrangement of (E)-1-Benzyloxy-2,3-Epoxyalkanes Tetrahedron 1998, 54, 11597– 11602 DOI: 10.1016/S0040-4020(98)00684-X
  There is no corresponding record for this reference.
238. 238
  Thurner, A.; Faigl, F.; Töke, L.; Mordini, A.; Valacchi, M.; Reginato, G.; Czira, G. Useful Base Promoted Elaborations of Oxiranyl Ethers Tetrahedron 2001, 57, 8173– 8180 DOI: 10.1016/S0040-4020(01)00790-6
  238
  Useful base promoted elaborations of oxiranyl ethers
  Thurner, A.; Faigl, F.; Toke, L.; Mordini, A.; Valacchi, M.; Reginato, G.; Czira, G.
  Tetrahedron (2001), 57 (38), 8173-8180CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
  Functionalized oxiranyl ethers can be regio- and stereoselectively converted into hydroxy oxetanes or cis-diols by treatment with organometallic bases. These two rearrangements can be conveniently carried out either using different reaction conditions starting from the oxirane or in two consecutive steps from the oxirane via the oxetane.
239. 239
  Mordini, A.; Bindi, S.; Pecchi, S.; Capperucci, A.; Degl’Innocent, A.; Reginato, G. A Selective and General Access to Trisubstituted Oxetanes J. Org. Chem. 1996, 61, 4466– 4468 DOI: 10.1021/jo9604595
  There is no corresponding record for this reference.
240. 240
  Mordini, A.; Valacchi, M.; Nardi, C.; Bindi, S.; Poli, G.; Reginato, G. A Selective Access to Amino Hydroxy Oxetanes J. Org. Chem. 1997, 62, 8557– 8559 DOI: 10.1021/jo9708607
  There is no corresponding record for this reference.
241. 241
  Mordini, A.; Bindi, S.; Capperucci, A.; Nistri, D.; Reginato, G.; Valacchi, M. Stereoselective Access to Hydroxy Oxetanes and Tetrahydrooxepines through Isomerization of Oxiranyl Ethers J. Org. Chem. 2001, 66, 3201– 3205 DOI: 10.1021/jo0005924
  241
  Stereoselective Access to Hydroxy Oxetanes and Tetrahydrooxepines through Isomerization of Oxiranyl Ethers
  Mordini, Alessandro; Bindi, Simona; Capperucci, Antonella; Nistri, Daniele; Reginato, Gianna; Valacchi, Michela
  Journal of Organic Chemistry (2001), 66 (9), 3201-3205CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Substituted trans-oxetanemethanols I (R = BuCH2, Me3CSi(Me)2OCH2; R1 = Ph, HC≡C) and cis-substituted tetrahydrooxepines II (R = H, BuCH2, Me3CSi(Me)2OCH2; R1 = H2C:CH) are prepd. regioselectively by lithiation of substituted glycidyl ethers III with lithium bases derived from either butyllithium or lithium diisopropylamide and potassium tert-butoxide. E.g., III (R = BuCH2; R1 = H2C:CH) was added to a THF soln. of hexane-free butyllithium and potassium tert-butoxide (prepd. at -78°) and stirred for 15 h at -50°; after quenching and workup, I (R = BuCH2; R1 = H2C:CH) was obtained in 65% isolated yield as a 98:2 mixt. of regioisomers (with the tetrahydrooxepine II) and as a 98:2 mixt. of stereoisomers. The regiochem. of nucleophilic cyclization depends upon the substitution next to the glycidyl ether oxygen; when the pendant group is either a Ph or ethynyl group, the cyclization gives oxetanemethanol derivs. selectively, while when the pendant group is a vinyl group, tetrahydrooxepine derivs. are obtained as the sole products. Superbase-promoted isomerization of oxiranyl ethers thus allows convenient access to oxetane and tetrahydrooxepane derivs with high regio- and stereoselectivities.
242. 242
  Faigl, F.; Thurner, A.; Tárkányi, G.; Kovári, J.; Mordini, A. Resolution and Enantioselective Rearrangements of Amino Group-Containing Oxiranyl Ethers Tetrahedron: Asymmetry 2002, 13, 59– 68 DOI: 10.1016/S0957-4166(02)00051-4
  There is no corresponding record for this reference.
243. 243
  Niitsuma, S.; Ichikawa, Y.; Kato, K.; Takita, T. Studies on the Total Synthesis of Oxetanocin; I. The First Synthesis of a Nucleoside Having Oxetanosyl-N-Glycoside Tetrahedron Lett. 1987, 28, 3967– 3970 DOI: 10.1016/S0040-4039(00)96433-5
  243
  Studies on the total synthesis of oxetanocin. I. The first synthesis of a nucleoside having oxetanosyl-N-glycoside
  Niitsuma, Setsuko; Ichikawa, Yuichiro; Kato, Kuniki; Takita, Tomohisa
  Tetrahedron Letters (1987), 28 (34), 3967-70CODEN: TELEAY; ISSN:0040-4039.
  The first synthesis of 9-(2-oxetanyl)adenine I, a key intermediate for the synthesis of the novel nucleoside oxetanocin (II), was achieved via cyclization between the allyloxy carbanion and the epoxy group in III.
244. 244
  Niitsuma, S.; Kato, K.; Takita, T. Studies on the Total Synthesis of Oxetanocin; II. Total Synthesis of Oxetanocin Tetrahedron Lett. 1987, 28, 4713– 4714 DOI: 10.1016/S0040-4039(00)96606-1
  244
  Studies on the total synthesis of oxetanocin. II. Total synthesis of oxetanocin
  Niitsuma, Setsuko; Ichikawa, Yuichiro; Kato, Kuniki; Takita, Tomohisa
  Tetrahedron Letters (1987), 28 (40), 4713-14CODEN: TELEAY; ISSN:0040-4039.
  Oxetanyladenine I, whose prepn. has been previously reported, was converted into oxetanocin (II) in 5 steps.
245. 245
  Maegawa, T.; Otake, K.; Hirosawa, K.; Goto, A.; Fujioka, H. Method for the Efficient Synthesis of Highly-Substituted Oxetan- and Azetidin-, Dihydrofuran- and Pyrrolidin-3-Ones and Its Application to the Synthesis of (±)-Pseudodeflectusin Org. Lett. 2012, 14, 4798– 4801 DOI: 10.1021/ol302096j
  There is no corresponding record for this reference.
246. 246
  Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A. 2-(Aryl-sulfonyl)oxetanes as Designer 3-Dimensional Fragments for Fragment Screening: Synthesis and Strategies for Functionalisation Chem. Commun. 2014, 50, 5203– 5205 DOI: 10.1039/C3CC46450D
  246
  2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation
  Morgan, Kate F.; Hollingsworth, Ian A.; Bull, James A.
  Chemical Communications (Cambridge, United Kingdom) (2014), 50 (40), 5203-5205CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  2-Sulfonyl-oxetanes were prepd., affording non-planar structures with desirable physicochem. properties for fragment based drug discovery. The oxetane motif was formed by an intramol. C-C bond formation. The fragments were further functionalized via organometallic intermediates at the intact oxetane and arom. rings.
247. 247
  Morgan, K. F.; Doran, R.; Croft, R. A.; Hollingsworth, I. A.; Bull, J. A. 2-Sulfinyl Oxetanes: Synthesis, Stability and Reactivity Synlett 2016, 27, 106– 110 DOI: 10.1055/s-0035-1560588
  There is no corresponding record for this reference.
248. 248
  Davis, O. A.; Bull, J. A. Recent Advances in the Synthesis of 2-Substituted Oxetanes Synlett 2015, 26, 1283– 1288 DOI: 10.1055/s-0034-1380412
  248
  Recent Advances in the Synthesis of 2-Substituted Oxetanes
  Davis, Owen A.; Bull, James A.
  Synlett (2015), 26 (10), 1283-1288CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
  A review. Recent interest in oxetanes in medicinal chem. and as synthetic intermediates has led to the development of a no. of methods for the synthesis of more functionalized and highly substituted oxetane derivs. Here we review cyclization approaches for the prepn. of 2-substituted oxetanes. Methods involving C-O bond formation, as well as recently developed C-C bond forming cyclization strategies are highlighted.
249. 249
  Davis, O. A.; Croft, R. A.; Bull, J. A. Synthesis of Diversely Functionalised 2,2-Disubstituted Oxetanes: Fragment Motifs in New Chemical Space Chem. Commun. 2015, 51, 15446– 15449 DOI: 10.1039/C5CC05740J
  249
  Synthesis of diversely functionalized 2,2-disubstituted oxetanes: fragment motifs in new chemical space
  Davis, Owen A.; Croft, Rosemary A.; Bull, James A.
  Chemical Communications (Cambridge, United Kingdom) (2015), 51 (84), 15446-15449CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  The synthesis of diversely functionalized oxetane derivs., e.g., I in new chem. space, was achieved via rhodium-catalyzed O-H insertion and C-C bond forming cyclization.
250. 250
  D’Auria, M.; Racioppi, R. Concepts of Stereoselective Photochemistry and a Case Study: The Paterno-Buchi Reaction Curr. Org. Chem. 2009, 13, 939– 954 DOI: 10.2174/138527209788452126
  250
  Concepts of stereoselective photochemistry and a case study: the Paterno-Buchi reaction
  D'Auria, Maurizio; Racioppi, Rocco
  Current Organic Chemistry (2009), 13 (9), 939-954CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
  A review. The main methods reported in literature to obtain stereoselective photochem. reaction is reviewed. The most important approached attempted to obtain stereoselective photochem. reaction are as follows. The use of diastereoselective photochem. reactions. The use of mols. with prevented mobility, and this approach can be obtained by the following. Introducing chiral auxiliary. Introducing chiral mols. in the reaction mixt. able to give complexes with a reduced mobility. Performing the reaction in organized media such as zeolites or cyclodextrins. Performing the reaction on single crystal. Performing the reaction on single crystals of mols. able to give crystal in chiral space group. Finally performing the reaction in solid phase on inclusion complexes of the substrate with chiral mols. Using chiral solvents and chiral light. Using chiral photosensitizers. The case of the diastereoselective Paterno-Buchi reaction on furan derivs. is also discussed.
251. 251
  Eftekhari-Sis, B.; Zirak, M. Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles Chem. Rev. 2015, 115, 151– 264 DOI: 10.1021/cr5004216
  251
  Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles
  Eftekhari-Sis, Bagher; Zirak, Maryam
  Chemical Reviews (Washington, DC, United States) (2015), 115 (1), 151-264CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  There is no expanded citation for this reference.
252. 252
  Bach, T. The Paterno-Büchi Reaction of 3-Heteroatom-Substituted Alkenes as a Stereoselective Entry to Polyfunctional Cyclic and Acyclic Molecules Liebigs Ann. Chem. 1997, 1997, 1627– 1634 DOI: 10.1002/jlac.199719970803
  There is no corresponding record for this reference.
253. 253
  Griesbeck, A. G.; Abe, M.; Bondock, S. Selectivity Control in Electron Spin Inversion Processes: Regio- and Stereochemistry of Paternò-Büchi Photocycloadditions as a Powerful Tool for Mapping Intersystem Crossing Processes Acc. Chem. Res. 2004, 37, 919– 928 DOI: 10.1021/ar040081u
  There is no corresponding record for this reference.
254. 254
  Abe, M.; Kawakami, T.; Ohata, S.; Nozaki, K.; Nojima, M. Mechanism of Stereo- and Regioselectivity in the Paternò-Büchi Reaction of Furan Derivatives with Aromatic Carbonyl Compounds: Importance of the Conformational Distribution in the Intermediary Triplet 1,4-Diradicals J. Am. Chem. Soc. 2004, 126, 2838– 2846 DOI: 10.1021/ja039491o
  There is no corresponding record for this reference.
255. 255
  Palmer, I. J.; Ragazos, I. N.; Bernardi, F.; Olivucci, M.; Robb, M. A. An MC-SCF Study of the (Photochemical) Paterno-Buchi Reaction J. Am. Chem. Soc. 1994, 116, 2121– 2132 DOI: 10.1021/ja00084a058
  255
  An MC-SCF Study of the (Photochemical) Paterno-Buechi Reaction
  Palmer, Ian J.; Ragazos, Ioannis N.; Bernardi, Fernando; Olivucci, Massimo; Robb, Michael A.
  Journal of the American Chemical Society (1994), 116 (5), 2121-32CODEN: JACSAT; ISSN:0002-7863.
  An MC-SCF/6-31G* study of the singlet and triplet Paterno-Buechi reaction (for the model system formaldehyde and ethylene) is presented. In addn. to the computation of the relevant min. and transition structures, the Born-Oppenheimer violation regions, where a fast decay from the singlet excited state (S1) to the ground state (S0) surface takes place, have been fully characterized by locating and optimizing the structure of two different S0/S1 conical intersections. The photochem. mechanisms of oxetane formation via carbon-carbon (C-C) and carbon-oxygen (C-O) attacks have both been investigated. For the C-C attack the singlet mechanism can be concerted as the decay to the ground state takes place in a point where the C-C bond is fully formed. Thus, starting from this decay point, the system can evolve directly to oxetane or produce a C-C bonded transient diradical intermediate. The C-O attack leads to a nonconcerted path only. In this case, the excited-state branch of the reaction coordinate terminates in a conical intersection point at a C-O distance of 1.77 Å before the diradical is fully formed. Thus, the system can evolve back to the reactant or produce a C-O bonded transient diradical intermediate that is isolated by very small barriers to fragmentation or ring-closure to oxetane. While the diradical structures corresponding to the two modes of attack differ in energy by only 8 kcal mol-1, the S1 to S0 decay point for C-C attack lies 33 kcal mol-1 below the corresponding point for C-O attack. The triplet diradicals have energies and geometries that are very similar to the singlets. Thus the authors predict that intersystem crossing from triplet to singlet will lead to the same diradical ground-state pathways that can be entered via singlet photochem.
256. 256
  Paterno-Büchi Reaction. In Comprehensive Organic Name Reactions and Reagents; Wang, Z., Ed.; John Wiley and Sons: 2010; pp 2126– 2130; DOI: DOI: 10.1002/9780470638859 .
  There is no corresponding record for this reference.
257. 257
  Bach, T.; Jödicke, K.; Kather, K.; Fröhlich, R. 1,3-Allylic Strain as a Control Element in the Paternò–Büchi Reaction of Chiral Silyl Enol Ethers: Synthesis of Diastereomerically Pure Oxetanes Containing Four Contiguous Stereogenic Centers J. Am. Chem. Soc. 1997, 119, 2437– 2445 DOI: 10.1021/ja963827v
  There is no corresponding record for this reference.
258. 258
  Bach, T.; Kather, K. Hydroxyl-Directed Reductive Cleavage of 3-Oxetanols as an Entry to Diastereomerically Pure 1,2-Diols J. Org. Chem. 1996, 61, 3900– 3901 DOI: 10.1021/jo952235c
  There is no corresponding record for this reference.
259. 259
  Bach, T. N-Acyl Enamines in the Paternò–Büchi Reaction: Stereoselective Preparation of 1,2-Amino Alcohols by C–C Bond Formation Angew. Chem., Int. Ed. Engl. 1996, 35, 884– 886 DOI: 10.1002/anie.199608841
  259
  N-Acyl enamines in the Paterno-Buechi reaction: stereoselective preparation of 1,2-amino alcohols by C-C bond formation
  Bach, Thorsten
  Angewandte Chemie, International Edition in English (1996), 35 (8), 884-886CODEN: ACIEAY; ISSN:0570-0833. (VCH)
  The Paterno-Buechi reaction of N-ethenylamides with benzaldehyde gave cis-N-(2-phenyl-3-oxetanyl)acetamides or cis-(2-phenyl-3-oxetanyl)carbamic acid esters. For example, the cyclization of 2,3-dihydro-1H-pyrrole-1-carboxylic acid Me ester (I) gave the fused oxazolidine II which upon hydrolytic ring cleavage gave cis-3-hydroxy-2-(phenylmethyl)-1-pyrrolidinecarboxylic acid Me ester.
260. 260
  Bach, T.; Brummerhop, H. Unprecedented Facial Diastereoselectivity in the Paternò–Büchi Reaction of - A Chiral Dihydropyrrole - A Short Total Synthesis of (+)-Preussin Angew. Chem., Int. Ed. 1998, 37, 3400– 3402 DOI: 10.1002/(SICI)1521-3773(19981231)37:24<3400::AID-ANIE3400>3.0.CO;2-3
  There is no corresponding record for this reference.
261. 261
  Bach, T.; Schröder, J. Photocycloaddition of N-Acyl Enamines to Aldehydes and Its Application to the Synthesis of Diastereomerically Pure 1,2-Amino Alcohols J. Org. Chem. 1999, 64, 1265– 1273 DOI: 10.1021/jo9819988
  261
  Photocycloaddition of N-Acyl Enamines to Aldehydes and Its Application to the Synthesis of Diastereomerically Pure 1,2-Amino Alcohols
  Bach, Thorsten; Schroeder, Juergen
  Journal of Organic Chemistry (1999), 64 (4), 1265-1273CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The regio- and stereoselective synthesis of protected cis-aminooxetanes is reported. The oxetanes were obtained by the photocycloaddn. of aliph. and arom. aldehydes to the corresponding enamides or enecarbamates. The enamine derivs. used in the Paterno-Buechi reaction were either com. available or prepd. from the corresponding acetaldehyde imines by acylation. The oxetane formation proceeded with good-to-excellent simple diastereoselectivity for arom. aldehydes (56-82% yield) and moderate selectivity for aliph. aldehydes (46-55% yield). The cis-3-aminooxetanes are precursors for syn- and anti-1,2-amino alcs. The relative configuration established in the photochem. step was retained upon nucleophilic ring opening between the oxygen atom and carbon atom C-4. By this means, syn-1,2-amino alcs. were available in good yields. In contrast, some N-Boc-protected cis-3-aminooxetanes were transformed into anti-1,2-amino alcs. Upon treatment with trifluoroacetic acid, they underwent an intramol. nucleophilic substitution at the carbon atom C-2 of the oxetane and oxazolidinones were formed. Because the substitution occurs with inversion of configuration, anti-1,2-amino alcs., e.g., ephedrine, are accessible.
262. 262
  Bach, T.; Schröder, J. The Paternò–Büchi Reaction of α-Alkyl-Substituted Enecarbamates and Benzaldehyde Synthesis 2001, 112, 1117– 1124 DOI: 10.1055/s-2001-15075
  There is no corresponding record for this reference.
263. 263
  Bach, T.; Brummerhop, H.; Harms, K. The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò–Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles Chem. - Eur. J. 2000, 6, 3838– 3848 DOI: 10.1002/1521-3765(20001016)6:20<3838::AID-CHEM3838>3.3.CO;2-T
  263
  The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buechi reactions of chiral 2-substituted 2,3-dihydropyrroles
  Bach, Thorsten; Brummerhop, Harm; Harms, Klaus
  Chemistry - A European Journal (2000), 6 (20), 3838-3848CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
  The N-alkoxycarbonyl substituted 2,3-dihydropyrroles are converted to 2-benzyl-3-pyrrolidinols by the Paterno-Buechi reaction followed by hydrogenolysis. Since the addn. of the photoexcited benzaldehyde at the unsatd. heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paterno-Buechi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin was conducted, which yielded the target compd. in a total yield of 11% over nine steps starting from L-pyroglutaminol.
264. 264
  Vogt, F.; Jödicke, K.; Schröder, J.; Bach, T. Paternò-Büchi Reactions of Silyl Enol Ethers and Enamides Synthesis 2009, 4268– 4273 DOI: 10.1055/s-0029-1217095
  264
  Paterno-Buechi reactions of silyl enol ethers and enamides
  Vogt, Florian; Joedicke, Kai; Schroeder, Juergen; Bach, Thorsten
  Synthesis (2009), (24), 4268-4273CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
  3-(Silyloxy)oxetanes are obtained by irradiating mixts. of arom. aldehydes and silyl enol ethers in benzene as the solvent. The reactions occur with high simple diastereoselectivity and, when R1 is chiral, with high facial diastereoselectivity. Under similar conditions, but in acetonitrile rather than benzene as the preferred solvent, the Paterno-Buechi reaction of N-acyl enamines (enamides) gives the corresponding protected 3-aminooxetanes. The cis-products are obtained with significant simple diastereoselectivity.
265. 265
  Bach, T. The Paternò-Büchi Reaction of N-Acyl Enamines and Aldehydes – The Development of a New Synthetic Method and its Application to Total Synthesis and Molecular Recognition Studies Synlett 2000, 2000 (12) 1699– 1707 DOI: 10.1055/s-2000-8668
  There is no corresponding record for this reference.
266. 266
  Griesbeck, A. G.; Franke, M.; Neudörfl, J.; Kotaka, H. Photocycloaddition of Aromatic and Aliphatic Aldehydes to Isoxazoles: Cycloaddition Reactivity and Stability Studies Beilstein J. Org. Chem. 2011, 7, 127– 134 DOI: 10.3762/bjoc.7.18
  266
  Photocycloaddition of aromatic and aliphatic aldehydes to isoxazoles: cycloaddition reactivity and stability studies
  Griesbeck, Axel G.; Franke, Marco; Neudoerfl, Joerg; Kotaka, Hidehiro
  Beilstein Journal of Organic Chemistry (2011), 7 (), 127-134, No. 18CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  The first photocycloaddns. of arom. and aliph. aldehydes to methylated isoxazoles are reported. The reactions lead solely to the exo-adducts with high regio- and diastereoselectivities. E.g., photocycloaddn of 3,4,5-trimethylisoxazole with PhCHO gave 50% exo-oxetane I. Ring methylation of the isoxazole substrates is crucial for high conversions and product stability. The 6-arylated bicyclic oxetanes, e.g. I, were characterized by X-ray structure analyses and showed the highest thermal stabilities. All oxetanes formed from isoxazoles were highly acid-sensitive and also thermally unstable. Cleavage to the original substrates is dominant and the isoxazole-derived oxetanes show type T photochromism.
267. 267
  Huang, C.; Yu, H.; Miao, Z.; Zhou, J.; Wang, S.; Fun, H.-K.; Xu, J.; Zhang, Y. Facile Synthesis of Spiroisoquinolines Based on Photocycloaddition of Isoquinoline-1,3,4-Trione with Oxazoles Org. Biomol. Chem. 2011, 9, 3629– 3631 DOI: 10.1039/c1ob05143a
  There is no corresponding record for this reference.
268. 268
  Bach, T.; Bergmann, H.; Harms, K. High Facial Diastereoselectivity in the Photocycloaddition of a Chiral Aromatic Aldehyde and an Enamide Induced by Intermolecular Hydrogen Bonding J. Am. Chem. Soc. 1999, 121, 10650– 10651 DOI: 10.1021/ja992209m
  268
  High Facial Diastereoselectivity in the Photocycloaddition of a Chiral Aromatic Aldehyde and an Enamide Induced by Intermolecular Hydrogen Bonding
  Bach, Thorsten; Bergmann, Hermann; Harms, Klaus
  Journal of the American Chemical Society (1999), 121 (45), 10650-10651CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Chiral arom. aldehydes I [R = H, Me] were prepd. from the Me esters and 3-HOC6H4CHO and underwent photochem. cycloaddn. with 3,4-dihydro-1H-2-pyridinone (II) to give the oxaazabicyclohexanones III after cleavage of the chiral auxiliary. I [R = H], which forms a 1:1 complex with II, gives (-)-III with high stereoselectivity, whereas the reaction with I [R = Me] is not stereoselective.
269. 269
  Bach, T.; Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K. The [2+2]-Photocycloaddition of Aromatic Aldehydes and Ketones to 3,4-Dihydro-2-Pyridones: Regioselectivity, Diastereoselectivity, and Reductive Ring Opening of the Product Oxetanes Chem. - Eur. J. 2001, 7, 4512– 4521 DOI: 10.1002/1521-3765(20011015)7:20<4512::AID-CHEM4512>3.0.CO;2-H
  269
  The [2+2]-photocycloaddition of aromatic aldehydes and ketones to 3,4-dihydro-2-pyridones: regioselectivity, diastereoselectivity, and reductive ring opening of the product oxetanes
  Bach, Thorsten; Bergmann, Hermann; Brummerhop, Harm; Lewis, Warren; Harms, Klaus
  Chemistry - A European Journal (2001), 7 (20), 4512-4521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
  3,4-Dihydro-2(1H)-pyridinone derivs. were prepd. and evaluated with respect to their use as alkene components in stereoselective Paterno-Buchi reactions. 3,4-Dihydro-2(1H)-pyridinone was shown to be a versatile synthetic building block that reacted with various photoexcited arom. carbonyl compds. (benzaldehyde, benzophenone, acetophenone, Me phenylglyoxylate, 3-pivaloyloxybenzaldehyde) with high regioselectivity and diastereoselectivity (51-63% yield). The products can be subjected to hydrogenolysis, opening a new and efficient route for the synthesis of 2-arylmethyl-3-piperidinols. As examples, oxetanes thus prepd. were hydrogenolytically cleaved. These oxetanes included (1R,6S,8R)-rel-8-phenyl-7-oxa-2-azabicyclo[4.2.0]octan-3-one and (1R,6S)-rel-8,8-diphenyl-7-oxa-2-azabicyclo[4.2.0]octan-3-one. The ability of 3,4-dihydro-2(1H)-pyridinone to bind to a chiral lactam host through two hydrogen bonds was used favorably to differentiate the enantiotopic faces of its double bond. The reactant prepd. and used in this case was (+)-(1R,5S,7S)-1,5,7-trimethyl-2-oxo-3-Azabicyclo[3.3.1]nonane-7-carboxylic acid 3-formylphenyl ester. In the photocycloaddn. to a chiral aldehyde, which was conducted at - 10°C in toluene, a high facial diastereoselectivity (>90% de, 56% yield) was recorded. The stereo-selectivity results from a 1:1 assocn. of 3,4-dihydro-2(1H)-pyridinone to the aldehyde. Other 4-substituted dihydropyridones, 3,4-dihydro-4-methyl-2(1H)-pyridinone, 3,4-dihydro-4-(1-methylethyl)-2(1H)-pyridinone, and 3,4-dihydro-4-phenyl-2(1H)-pyridinone, were found to be less suited for potential use in photochem. The yields and facial diastereoselectivities recorded in their photocycloaddn. to benzophenone remained low.
270. 270
  Nehrings, A.; Scharf, H.-D.; Runsink, J. Photochemical Synthesis of an L-Erythrose Building Block and Its Use in the Preparation of Methyl 2,3,O-Isopropylidene-β-L-Apio-L-Furanoside Angew. Chem., Int. Ed. Engl. 1985, 24, 877– 878 DOI: 10.1002/anie.198508771
  There is no corresponding record for this reference.
271. 271
  Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. Hydroxy-Directed Regio- and Diastereoselective [2+2] Photocycloaddition (Paternò–Büchi Reaction) of Benzophenone to Chiral Allylic Alcohols J. Am. Chem. Soc. 2000, 122, 2958– 2959 DOI: 10.1021/ja994279z
  There is no corresponding record for this reference.
272. 272
  Hambalek, R.; Just, G. A Short Synthesis of (±)-Oxetanocin Tetrahedron Lett. 1990, 31, 5445– 5448 DOI: 10.1016/S0040-4039(00)97868-7
  272
  A short synthesis of (±)-oxetanocin
  Hambalek, Robert; Just, George
  Tetrahedron Letters (1990), 31 (38), 5445-8CODEN: TELEAY; ISSN:0040-4039.
  The photoadduct I of 2-methylfuran and propionyloxyacetaldehyde was transformed in a one-pot reaction to oxetane II, which gave oxetanocin and epioxetanocin.
273. 273
  Iriondo-Alberdi, J.; Perea-Buceta, J. E.; Greaney, M. F. A Paternò–Büchi Approach to the Synthesis of Merrilactone A Org. Lett. 2005, 7, 3969– 3971 DOI: 10.1021/ol0514496
  There is no corresponding record for this reference.
274. 274
  Xue, J.; Zhang, Y.; Wu, T.; Fun, H.-K.; Xu, J.-H. Photoinduced [2+2] Cycloadditions (the Paternò–Büchi reaction) of 1H-1-Acetylindole-2,3-dione with Alkenes J. Chem. Soc. Perkin Trans. 1 2001, 183– 191 DOI: 10.1039/b005576j
  There is no corresponding record for this reference.
275. 275
  Matsumura, K.; Mori, T.; Inoue, Y. Wavelength Control of Diastereodifferentiating Paternò–Büchi Reaction of Chiral Cyanobenzoates with Diphenylethene through Direct versus Charge-Transfer Excitation J. Am. Chem. Soc. 2009, 131, 17076– 17077 DOI: 10.1021/ja907156j
  There is no corresponding record for this reference.
276. 276
  Matsumura, K.; Mori, T.; Inoue, Y. Solvent and Temperature Effects on Diastereodifferentiating Paternò–Büchi Reaction of Chiral Alkyl Cyanobenzoates with Diphenylethene upon Direct versus Charge-Transfer Excitation J. Org. Chem. 2010, 75, 5461– 5469 DOI: 10.1021/jo101332x
  There is no corresponding record for this reference.
277. 277
  D’Annibale, A.; D’Auria, M.; Prati, F.; Romagnoli, C.; Stoia, S.; Racioppi, R.; Viggiani, L. Paternò-Büchi Reaction versus Hydrogen Abstraction in the Photochemical Reactivity of Alkenyl Boronates with Benzophenone Tetrahedron 2013, 69, 3782– 3795 DOI: 10.1016/j.tet.2013.03.068
  There is no corresponding record for this reference.
278. 278
  Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Flow Photochemistry: Old Light through New Windows Beilstein J. Org. Chem. 2012, 8, 2025– 2052 DOI: 10.3762/bjoc.8.229
  278
  Flow photochemistry: Old light through new windows
  Knowles, Jonathan P.; Elliott, Luke D.; Booker-Milburn, Kevin I.
  Beilstein Journal of Organic Chemistry (2012), 8 (), 2025-2052, No. 229CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  A review. Synthetic photochem. carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilized technique in general org. synthesis. Recent developments in flow photochem. have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in org. photochem., allowing a comparison of the various reactor types to be made.
279. 279
  Fukuyama, T.; Hino, Y.; Kamata, N.; Ryu, I. Quick Execution of [2+2] Type Photochemical Cycloaddition Reaction by Continuous Flow System Using a Glass-Made Microreactor Chem. Lett. 2004, 33, 1430– 1431 DOI: 10.1246/cl.2004.1430
  There is no corresponding record for this reference.
280. 280
  Fukuyama, T.; Kajihara, Y.; Hino, Y.; Ryu, I. Continuous Microflow [2+2] Photocycloaddition Reactions Using Energy-Saving Compact Light Sources J. Flow Chem. 2011, 1, 40– 45 DOI: 10.1556/jfchem.2011.00007
  280
  Continuous microflow [2 + 2] photocycloaddition reactions using energy-saving compact light sources
  Fukuyama, Takahide; Kajihara, Yoshito; Hino, Yoshiko; Ryu, Ilhyong
  Journal of Flow Chemistry (2011), 1 (), 40-45CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
  Photocycloaddn. of cyclohexenones with vinyl acetates or vinyl ethers and the Paterno-Buchi reaction were carried out using photomicroreactors in combination with compact light sources such as low-power black lights and UV LEDs. The obsd. high efficiency holds promise as an energy-saving protocol for photoinduced [2 + 2] cycloaddn. reactions.
281. 281
  Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B. Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity Chem. - Eur. J. 2014, 20, 15226– 15232 DOI: 10.1002/chem.201404347
  281
  Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity
  Elliott, Luke D.; Knowles, Jonathan P.; Koovits, Paul J.; Maskill, Katie G.; Ralph, Michael J.; Lejeune, Guillaume; Edwards, Lee J.; Robinson, Richard I.; Clemens, Ian R.; Cox, Brian; Pascoe, David D.; Koch, Guido; Eberle, Martin; Berry, Malcolm B.; Booker-Milburn, Kevin I.
  Chemistry - A European Journal (2014), 20 (46), 15226-15232CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The use of flow photochem. and its apparent superiority over batch has been reported by a no. of groups in recent years. To rigorously det. whether flow does indeed have an advantage over batch, a broad range of synthetic photochem. transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an av. productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chem. was demonstrated in the scale(coating process)-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.
282. 282
  Terao, K.; Nishiyama, Y.; Kakiuchi, K. Highly Efficient Asymmetric Paternò–Büchi Reaction in a Microcapillary Reactor Utilizing Slug Flow J. Flow Chem. 2014, 4, 35– 39 DOI: 10.1556/JFC-D-13-00035
  282
  Highly efficient asymmetric Paterno-Buchi reaction in a microcapillary reactor utilizing slug flow
  Terao, Kimitada; Nishiyama, Yasuhiro; Kakiuchi, Kiyomi
  Journal of Flow Chemistry (2014), 4 (1), 35-39, 5CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
  An asym. Paterno-Buchi-type photoreaction between 2,3-dimethyl-2-butene and benzoylformic acid ester with a chiral menthyl auxiliary was studied in a continuous-flow microcapillary reactor. The fluorinated ethylene propylene microcapillary reactor using normal one-layer flow mode gave oxetane products with better efficiency than the batch system. In addn., the slug flow mode in microcapillary reactor using inactive reagent, N2 gas or H2O, improved the reaction efficiency dramatically because of synergistic light dispersion, stirring and thin layer film effects. The reaction efficiencies under each condition were discussed as energy efficiencies calcd. from reactors parameters.
283. 283
  Mikami, K.; Aikawa, K.; Aida, J. Fragment-Based Reaction Discovery of Non-Ene-Type Carbon-Carbon Bond-Forming Reactions: Catalytic Asymmetric Oxetane Synthesis by Screening Olefinic Reactants without Allylic Hydrogen Synlett 2011, 2011, 2719– 2724 DOI: 10.1055/s-0031-1289540
  There is no corresponding record for this reference.
284. 284
  Aikawa, K.; Hioki, Y.; Shimizu, N.; Mikami, K. Catalytic Asymmetric Synthesis of Stable Oxetenes via Lewis Acid-Promoted [2+2] Cycloaddition J. Am. Chem. Soc. 2011, 133, 20092– 20095 DOI: 10.1021/ja2085299
  284
  Catalytic Asymmetric Synthesis of Stable Oxetenes via Lewis Acid-Promoted [2 + 2] Cycloaddition
  Aikawa, Kohsuke; Hioki, Yuta; Shimizu, Natsumi; Mikami, Koichi
  Journal of the American Chemical Society (2011), 133 (50), 20092-20095CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A highly enantioselective and atom-economical [2 + 2] cycloaddn. of various alkynes with trifluoropyruvate using a dicationic (S)-BINAP-Pd catalyst has been established. This is the first enantioselective synthesis of stable oxetene derivs., e.g., I, whose structure has been clarified by X-ray anal. This catalytic process offers a practical synthetic method for oxetene derivs. (catalyst loading: up to 0.1 mol %), which can serve as novel chiral building blocks for pharmaceuticals and agrochems. and can also be transformed into a variety of enantiomerically enriched CF3-substituted compds. with high stereoselectivity.
285. 285
  Aikawa, K.; Hioki, Y.; Mikami, K. Highly Enantioselective Alkynylation of Trifluoropyruvate with Alkynylsilanes Catalyzed by the BINAP–Pd Complex: Access to α-Trifluoromethyl-Substituted Tertiary Alcohols Org. Lett. 2010, 12, 5716– 5719 DOI: 10.1021/ol102541s
  285
  Highly Enantioselective Alkynylation of Trifluoropyruvate with Alkynylsilanes Catalyzed by the BINAP-Pd Complex: Access to α-Trifluoromethyl-Substituted Tertiary Alcohols
  Aikawa, Kohsuke; Hioki, Yuta; Mikami, Ko-ichi
  Organic Letters (2010), 12 (24), 5716-5719CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  A highly enantioselective alkynylation catalyzed by the dicationic (S)-BINAP-Pd complex with a variety of alkynylsilanes and trifluoropyruvate is described. The catalytic reaction is applicable to highly enantioselective addn. of polyyne to trifluoropyruvate to construct α-trifluoromethyl-substituted tertiary alcs., e.g., I as enantiomerically enriched forms. The alkynyl products can be converted into a chiral allene bearing a trifluoromethyl group.
286. 286
  Baum, K.; Berkowitz, P. T.; Grakauskas, V.; Archibald, T. G. Synthesis of Electron-Deficient Oxetanes. 3-Azidooxetane, 3-Nitrooxetane, and 3,3-Dinitrooxetane J. Org. Chem. 1983, 48, 2953– 2956 DOI: 10.1021/jo00166a003
  286
  Synthesis of electron-deficient oxetanes. 3-Azidooxetane, 3-nitrooxetane, and 3,3-dinitrooxetane
  Baum, Kurt; Berkowitz, Phillip T.; Grakauskas, Vytautas; Archibald, Thomas G.
  Journal of Organic Chemistry (1983), 48 (18), 2953-6CODEN: JOCEAH; ISSN:0022-3263.
  Oxetane I (R = OH, R1 = H) was prepd. by addn. of HOAc to epichlorohydrin, protection of the resulting alc. as an acetal, hydrolysis, ring closure, and removal of the protecting group. I (R = N3, R1 = H) was prepd. from I (R = 4-MeC6H4SO3, R1 = H) and NaN3. Redn. of the azide with Ph3P or H gave I (R = NH2, R1 = H), and oxidn. of the amine with 3-ClC6H4C(O)OOH gave I (R = NO2, R1 = H). Oxidative nitration or reaction with C(NO2)4 gave I (R = R1 = NO2). I (R = N3, R1 = H; R = R1 = NO2) were polymd. with Lewis acids.
287. 287
  Wojtowicz, J. A.; Polak, R. J. 3-Substituted Oxetanes J. Org. Chem. 1973, 38, 2061– 2066 DOI: 10.1021/jo00951a020
  287
  3-Substituted oxetanes
  Wojtowicz, J. A.; Polak, R. J.
  Journal of Organic Chemistry (1973), 38 (11), 2061-6CODEN: JOCEAH; ISSN:0022-3263.
  3-Allyloxyoxetane was isomerized with tert-BuOK to give 85-90% 3-propenoxyoxetane (I) (96% cis). I was cleaved by acid to produce 84% 3-oxetanol. Oxetanone is formed either by oxidn. of oxetanol with chromic oxide-pyridine complex or by heating oxetyl tosylate in Me2SO. Heating oxetyl tosylate above 150° with alkali halides in triethylene glycol gave 75-85% 3-halooxetanes. A lower yield (10-20%) of 3-chlorooxetane was obtained when SOCl2 was reacted with 3-oxetanol. Reaction of iodooxetane with Et2NH at 200° gave 3-dimethylaminooxetane. Oxetyl acetate was prepd. in 84% yield by transesterification of oxetanol with allyl acetate. Transesterification of oxetanol with Et acrylate gave a low yield of oxetyl acrylate; the main product was Et 3-(3-oxetoxy)propionate. The acetate and acrylate esters were also prepd. by acylation of oxetanol.
288. 288
  Estrada, A. A.; Chan, B. K.; Baker-Glenn, C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chen, H.; Dominguez, S. L.; Dotson, J.; Drummond, J. Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors J. Med. Chem. 2014, 57, 921– 936 DOI: 10.1021/jm401654j
  288
  Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
  Estrada, Anthony A.; Chan, Bryan K.; Baker-Glenn, Charles; Beresford, Alan; Burdick, Daniel J.; Chambers, Mark; Chen, Huifen; Dominguez, Sara L.; Dotson, Jennafer; Drummond, Jason; Flagella, Michael; Fuji, Reina; Gill, Andrew; Halladay, Jason; Harris, Seth F.; Heffron, Timothy P.; Kleinheinz, Tracy; Lee, Donna W.; Pichon, Claire E. Le; Liu, Xingrong; Lyssikatos, Joseph P.; Medhurst, Andrew D.; Moffat, John G.; Nash, Kevin; Scearce-Levie, Kimberly; Sheng, Zejuan; Shore, Daniel G.; Wong, Susan; Zhang, Shuo; Zhang, Xiaolin; Zhu, Haitao; Sweeney, Zachary K.
  Journal of Medicinal Chemistry (2014), 57 (3), 921-936CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small mol. inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition. Using previously reported aminopyrazole I as a lead mol., we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 and GNE-9605 as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclin. efficacy and safety studies.
289. 289
  Wang, Z.; Chen, Z.; Sun, J. Catalytic Enantioselective Intermolecular Desymmetrization of 3-Substituted Oxetanes Angew. Chem., Int. Ed. 2013, 52, 6685– 6688 DOI: 10.1002/anie.201300188
  289
  Catalytic Enantioselective Intermolecular Desymmetrization of 3-Substituted Oxetanes
  Wang, Zhaobin; Chen, Zhilong; Sun, Jianwei
  Angewandte Chemie, International Edition (2013), 52 (26), 6685-6688CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Under optimized reaction conditions, the synthesis of the target compds. was achieved using (11aR)-10,11,12,13-tetrahydro-5-hydroxy-3,7-di(9-phenanthrenyl)diindeno[7,1-de:1',7'-fg][1,3,2]dioxaphosphocin 5-oxide (chiral cyclic phosphate) as a catalyst. A stereoselective ring opening reaction of 3-(phenyl)oxetane (I) with 2(3H)-benzothiazolethione [thiol, 2-(mercapto)benzothiazole] gave a chiral mercapto alc. (II).
290. 290
  Degnan, A. P.; Maxwell, D.; Hill, M. D.; Fang, H.; Parker, M. F.; Yang, F.; Bronson, J. J.; Macor, J. E. (Bristol-Myers Squibb). Oxazolidinones as modulators of mglur5. International Patent WO 2015054103 A1, 2015.
  There is no corresponding record for this reference.
291. 291
  Blomgren, P. A.; Currie, K. S.; Kropf, J. E.; Lee, S. H.; Lo, J. R.; Mitchell, S. A.; Schmitt, A. C.; Xiong, J.-M.; Xu, J.; Zhou, Z. (Gilead Sciences Inc.). SYK Inhibitors. U.S. Patent US 2015175616 A1, 2015.
  There is no corresponding record for this reference.
292. 292
  Collins, M. R.; Kania, R. S.; Kumpf, R. A.; Kung, P.-P.; Richter, D. T.; Sutton, S. C.; Wythes, M. J. (Pfizer Inc.). Substituted Dihydroisoquinolinone Compounds. International Patent WO 2015193765 A1, 2015.
  There is no corresponding record for this reference.
293. 293
  Kozikowski, A. P.; Fauq, A. H. Synthesis of Novel Four-Membered Ring Amino Acids as Modulators of the N-Methyl-D-Aspartate (NMDA) Receptor Complex Synlett 1991, 1991, 783– 784 DOI: 10.1055/s-1991-20873
  There is no corresponding record for this reference.
294. 294
  Duffey, M. O.; England, D. B.; Hu, Z.; Ito, M.; Langston, S. P.; Mcintyre, C.; Mizutani, H.; Xu, H. (Millennium Pharmaceuticals). Heteroaryl Inhibitors of Sumo Activating Enzyme. International Patent WO 2015002994 A2, 2015.
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295. 295
  Hubschwerlen, C.; Ochala, E.; Specklin, J.-L.; Surivet, J.-P.; Mirre, A.; Chapoux, G.; Gauvin, J.-C. (Actelion Pharmaceuticals Ltd.). Antibacterial 1H-Indazole and 1H-Indole Derivatives. International Patent WO 2015091741 A1, 2015.
  There is no corresponding record for this reference.
296. 296
  Steeneck, C.; Kinzel, O.; Gege, C.; Kleymann, G.; Hoffmann, T. (Phenex Pharmaceuticals). Pyrrolo Sulfonamide Compounds for Modulation of Orphan Nuclear Receptor RAR-Related Orphan Receptor-Gamma (Rorgamma, NR1F3) Activity and for the Treatment of Chronic Inflammatory and Autoimmune Disease. International Patent WO 2012139775 A1, 2012.
  There is no corresponding record for this reference.
297. 297
  Sharma, R.; Halder, S.; Kumar, S.; Mascarenhas, M. (Piramal Enterprises ). Substituted Heterocyclic Derivatives as GPR Agonists and Uses Thereof. International Patent WO 201528960, 2015.
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298. 298
  Boehme, T.; Engel, C.; Guessregen, S.; Haack, T.; Ritter, K.; Tschank, G. (Sanofi). Novel Substituted Phenyl-Oxathiazine Derivatives, Methods for Producing Them, Drugs Containing Said Compounds and the Use Thereof. International Patent WO 2012120057 A1, 2013.
  There is no corresponding record for this reference.
299. 299
  Reed, M. A.; Wood, T. K.; Banfield, S. C.; Barden, C. J. (Treventis Corporation). Benzofuran Anti-Amyloid Compounds and Methods. International Patent WO 2014031873 A2, 2014.
  There is no corresponding record for this reference.
300. 300
  Ahn, K.; Boehm, M.; Cabral, S.; Carpino, P. A.; Futatsugi, K.; Hepworth, D.; Kung, D. W.; Orr, S.; Wang, J. (Pfizer Inc.). Diacylglycerol Acyltransferase 2 Inhibitors. International Patent WO 2013150416 A1, 2013.
  There is no corresponding record for this reference.
301. 301
  Bhattacharya, S.; Cameron, K.; Dowling, M. S.; Fernando, D. P.; Ebner, D. C.; Filipski, K. J.; Kung, D. W.-S.; Lee, E. C. Y.; Smith, A. C.; Tu, M. M. (Pfizer Inc.). Indole and Indazole Compounds That Activate AMPK. International Patent WO 2013153479 A1, 2013.
  There is no corresponding record for this reference.
302. 302
  Frank-Foltyn, R.; Christoph, T.; Schiene, K.; De Vry, J.; Damann, N.; Lesch, B.; Bahrenberg, G.; Saunders, D. J.; Stockhausen, H.; Kim, Y.-S.; Kim, M.-S.; Lee, J. (Grünenthal GmbH). Substituted Pyrazolyl-Based Carboxamide and Urea Derivatives Bearing a Phenyl Moiety Substituted with an O-Containing Group as Vanilloid Receptor Ligands. International Patent WO 201368461 A1, 2013.
  There is no corresponding record for this reference.
303. 303
  Knust, H.; Nettekoven, M.; Pinard, E.; Roche, O.; Rogers-Evans, M. (F. Hoffmann-La Roche). Monoamide Derivatives as Orexin Receptor Antagonists. International Patent WO 2009016087 A1, 2009.
  There is no corresponding record for this reference.
304. 304
  Leftheris, K.; Zhuang, L.; Tice, C. M.; Singh, S. B.; Ye, Y.; Xu, Z.; Himmelsbach, F.; Eckhardt, M. (Vitae Pharmaceuticals Inc.). Substituted 5-, 6- and 7-Membered Heterocycles, Medicaments Containing Such Compounds and Their Use. International Patent WO 2011159760 A1, 2011.
  There is no corresponding record for this reference.
305. 305
  Hadd, M. J.; Holladay, M. W.; Rowbottom, M. (Ambit Biosciences Corp.). 7-Cyclylquinazoline Derivatives and Methods of Use Thereof. International Patent WO 201230912 A1, 2012.
  There is no corresponding record for this reference.
306. 306
  Dotson, J.; Heald, R. A.; Heffron, T.; Jones, G. E.; Krintel, S. L.; Mclean, N. J.; Ndubaku, C.; Olivero, A. G.; Salphati, L.; Wang, L.; Wei, B. (F. Hoffman-La Roche AG). Tricyclic PI3K Inhibitor Compounds and Methods of Use. International Patent WO 2012082997 A1, 2012.
  There is no corresponding record for this reference.
307. 307
  Dai, M.; Kelleher, J.; Yusuff, N.; Peukert, S.; Perez, L. B.; Miller-Moslin, K.; McEwan, M. A.; Llamas, L.; Lei, J.; Karki, R.; He, F.; Jain, R. K. (Novartis AG). Organic Compounds and Their Uses. International Patent WO 2008110611 A1, 2008.
  There is no corresponding record for this reference.
308. 308
  Allan, M.; Chamoin, S.; Hu, Q.-Y.; Imase, H.; Papillon, J. (Novartis AG). Aryl-Pyridine Derivatives as Aldosterone Synthase Inhibitors. International Patent WO 201161168 A1, 2011.
  There is no corresponding record for this reference.
309. 309
  Velaparthi, U.; Frennesson, D. B.; Saulnier, M. G.; Austin, J. F.; Huang, A.; Balog, J. A.; Vyas, D. M. (Bristol-Myers Squibb Co.). Azaindazole Compounds. International Patent WO 201209510 A1, 2012.
  There is no corresponding record for this reference.
310. 310
  Fessard, T.; Li, D.-B.; Barbaras, D.; Wolfrum, S.; Carreira, E. (Lipideon Biotechnology AG). Pharmaceutical Hypochloresterolemic Compositions. International Patent WO 2010100255 A1, 2010.
  There is no corresponding record for this reference.
311. 311
  Patterson, B. D.; Lu, Q.; Aggen, J. B.; Dozzo, P.; Kasar, R. A.; Linsell, M. S.; Kane, T. R.; Gliedt, M. J.; Hildebrandt, D. J.; Mcenroe, G. A.; Cohen, F.; Moser, H. E. (Achaogen, Inc.). Antibacterial Agents. International Patent WO 2013170030 A1, 2012.
  There is no corresponding record for this reference.
312. 312
  An, J.-H.; Yun, H.; Shin, S.; Shin, S. Gold-Catalyzed Regioselective Meyer-Schuster Rearrangement and Ring Expansion Cascade Leading to α-Hydroxy-α-Vinylcyclopentanones Adv. Synth. Catal. 2014, 356, 3749– 3754 DOI: 10.1002/adsc.201400569
  There is no corresponding record for this reference.
313. 313
  Che, J.; Chen, B.; Ding, Q.; Hao, X.; He, X.; Jiang, S.; Jin, Q.; Jin, Y.; Liu, H.; Liu, Y.; Okram, B.; Uno, T.; Wu, X.; Yang, K.; Zhu, X. (IRM LLC). 2,7-Napthyridin-1-one Derivatives as SYK Kinase Inhibitors. International Patent WO 201114515 A1, 2011.
  There is no corresponding record for this reference.
314. 314
  Santella, J. B.; Kumar, S. R.; Duncia, J. V.; Gardner, D. S.; Paidi, V. R.; Nair, S. K.; Hynes, J.; Wu, H.; Murugesan, N.; Sarkunam, K.; Heteroaryl Substituted Nicotinamide Compounds. International Patent WO 201503453 A1, 2015.
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  Fensholdt, J.; Havez, S. E.; Nøerremark, B. (Leo Pharma A/S). Novel Cyclic Hydrocarbon Compounds for the Treatment of Diseases. International Patent WO 2009065406 A2, 2009.
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316. 316
  Alexander, R. P.; Bentley, J. M.; Brace, G. N.; Brookings, D. C.; Chovatia, P. T.; Deboves, H. J. C.; Johnstone, C.; Jones, E. P.; Kroeplien, B.; Lecomte, F. C.; Madden, J.; Miller, C. A.; Porter, J. R.; Selby, M. D.; Shaw, M. A.; Vaidya, D. G.; Yule, I. A. (UCB Biopharma SPRL). Fused Imidazole and Pyrazole Derivatives as Modulators of TNF Activity. International Patent WO 201586506 A1, 2015.
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  Gavelle, O.; Grether, U.; Kimbara, A.; Nettekoven, M.; Roever, S.; Rogers-Evans, M.; Rombach, D.; Schulz-Gasch, T. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Novel Pyridine Derivatives. International Patent WO 2014154612 A1, 2014.
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318. 318
  Grether, U.; Kimbara, A.; Nettekoven, M.; Ricklin, F.; Roever, S.; Rogers-Evans, M.; Rombach, D.; Schulz-Gasch, T.; Westphal, M. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Pyridine-2-amides Useful as CB2 Agonists. International Patent WO 201486805 A1, 2014.
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319. 319
  Burger, M.; Ding, Y.; Han, W.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Tanner, H.; Wan, L. (Novartis AG). Novel Aminothiazole Carboxamides as Kinase Inhibitors. International Patent WO 2014033630 A1, 2014.
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320. 320
  Dehnhardt, C. M.; Chowdhury, S.; Focken, T.; Grimwood, M. E.; Hemeon, I. W.; Safina, B.; Sutherlin, D. P. (Genentech Inc.). N-Substituted Benzamides and Methods of Use Thereof. International Patent WO 2014008458 A2, 2014.
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321. 321
  Härter, M.; Beck, H.; Ellinghaus, P.; Berhöester, K.; Greschat, S.; Thierauch, K.-H.; Süssmeier, F. (Bayer Schering Pharma AG). Hetereocyclically Substituted Aryl Compounds as HIF Inhibitors. International Patent WO 2010054763 A1, 2010.
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322. 322
  Burger, M.; Nishiguchi, G.; Machajewski, T. D.; Rico, A.; Simmons, R. L.; Smith, A. R.; Tamez, Jr., V.; Tanner, H.; Wan, L. Novel Kinase Inhibitors. U.S. Patent US 2012225062 A1, 2012.
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323. 323
  Pei, Z.; Lyssikatos, J. P.; Lau, K. H. L.; Lee, W.; Robarge, K. D. (F. Hoffmann-La Roche AG). N-9 Substituted Purine Compounds Compositions and Methods of Use. International Patent WO 2011058027 A1, 2011.
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324. 324
  Ackermann, J.; Conte, A.; Hunziker, D.; Neidhart, W.; Nettekoven, M.; Schulz-Gasch, T.; Wertheimer, S. (F. Hoffmann-La Roche). Azacyclic Spiroderivatives as HSL Inhibitors. International Patent WO 2010130665 A1, 2010.
  There is no corresponding record for this reference.
325. 325
  Billen, D.; Curtis, M.; Ewin, R. A.; Goodwin, R. M.; Johnson, P. A.; Johnson, T. A.; Kyne, G. M.; Maddux, T. M.; Sheehan, S. M. K.; Vairagoundar, R. (Zoetis LLC). Phenicol Antibacterial Agents. U.S. Patent US 2014088046 A1, 2014.
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326. 326
  Skerratt, S. E.; Bagal, S. K.; Swain, N. A.; Omoto, K.; Andrews, M. D. (Pfizer Ltd.). N-Acylpiperidine Ether Tropomyosin-Related Kinase Inhibitors. International Patent WO 2015092610 A1, 2015.
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327. 327
  Heimann, A.; Dahmann, G.; Grundl, M.; Mueller, S. G.; Wellenzohn, B. (Boehringer Ingelheim International GmbH). Piperazine Derivatives and Their Use as Positive Allosteric Modulators of MGLU5 Receptors. International Patent WO 2013087805 A1, 2013.
  There is no corresponding record for this reference.
328. 328
  Blake, J. F.; Brandhuber, B. J.; Haas, J.; Newhouse, B.; Thomas, A. A.; Winski, S. L. (Array Biopharma Inc.). N-(Arylalkyl)-N′-pyrazoleurea, Thiourea, Guanidine and Cyanoguanidine Compounds as TrkA Kinase Inhibitors. International Patent WO 2014078331 A1, 2014.
  There is no corresponding record for this reference.
329. 329
  Alexander, R. P.; Calmiano, M. D.; Defays, S.; Durieu, V.; Deligny, M.; Heer, J. P.; Jackson, V. E.; Keyaerts, J.; Kroeplien, B.; Maccoss, M.; Sabnis, Y. A.; Selby, M. D.; Swinnen, D. L. L.; Van Houtvin, N.; Zhu, Z. (UCB Biopharma SPRL). Fused Tricylic Benzimidazoles Derivatives As Modulators of TNF Activity. International Patent WO 2015086525 A1, 2015.
  There is no corresponding record for this reference.
330. 330
  Boyer, S.; Härter, M.; Patel, M.; Wickens, P.; Kumarasinghe, E. S.; Hess-Stumpp, H.; Paulus, P.; Greschat, S.; Beck, H.; Thierauch, K.-H.; Bhargava, A. K. (Bayer Healthcare AG; Bayer Schering Pharma AG). Inhibitors of Hypoxia Inducible Factor (HIF) Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis. International Patent WO 2008141731 A2, 2008.
  There is no corresponding record for this reference.
331. 331
  Härter, M.; Beck, H.; Ellinghaus, P.; Berhöester, K.; Greschat, S.; Thierauch, K.-H.; Süssmeier, F. (Bayer Schering Pharma AG). Heteroaromatic Compounds for Use as HIF Inhibitors. U.S. Patent US 2011301122 A1, 2011.
  There is no corresponding record for this reference.
332. 332
  Härter, M.; Beck, H.; Ellinghaus, P.; Berhöester, K.; Greschat, S.; Thierauch, K.-H. (Bayer Schering Pharma AG). Aryl Compounds with Aminoalkyl Substituents and Their Use. U.S. Patent US 20110312930 A1, 2011.
  There is no corresponding record for this reference.
333. 333
  Heimann, A.; Dahmann, G.; Grundl, M.; Mueller, S. G.; Wellenzohn, B. (Boehringer Ingelheim International GmbH). Novel Compounds. U.S. Patent US 20130158042 A1, 2013.
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334. 334
  Altman, M.; Christopher, M.; Grimm, J. B.; Haidle, A.; Konrad, K.; Lim, J.; Maccoss, R. N.; Machacek, M.; Osimboni, E.; Otte, R. D.; Siu, T.; Spencer, K.; Taoka, B.; Tempest, P.; Wilson, K.; Woo, H. C.; Young, J.; Zabierek, A. (Merck and Co., Inc.). Inhibitors of Janus Kinases. International Patent WO 2008156726 A1, 2008.
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335. 335
  Stock, N. S.; Chen, A. C.-Y.; Bravo, Y. M.; Jacintho, J. D.; Baccei, J. M.; Stearns, B. A.; Clark, R. C.; Truonh, Y. P. (Inception 2, Inc.). Triazolone Compounds and Uses Thereof. International Patent WO 2013134562 A1, 2013.
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336. 336
  Man, A.; Petrus, A.; Sterrenburg, J.-G.; Raaijmakers, H. C. A.; Kaptein, A.; Oubrie, A. A.; Rewinkel, J.; Bernardus, M.; Jans, C. G. J. M.; Wijkmans, J. C. H. M.; Barf, T. A.; Gao, X.; Boga, S. B.; Yao, X.; Zhu, H. Y.; Cooper, A. B.; Kim, R. M. (MSD Oss BV). (4-(5-Membered Fused Pyridinyl)benzamides as BTK-Inhibitors. European Patent EP 2548877 A1, 2013.
  There is no corresponding record for this reference.
337. 337
  Kim, R. M.; Liu, J.; Gao, X.; Boga, S. B.; Guiadeen, D.; Kozlowski, J. A.; Yu, W.; Anand, R.; Yu, Y.; Selyutin, O. B.; Gao, Y.-D.; Wu, H.; Liu, S.; Yang, C.; Wang, H. (Merck Sharp & Dohme Corp.). BTK Inhibitors. U.S. Patent US 2014206681 A1, 2014.
  There is no corresponding record for this reference.
338. 338
  Luo, G.; Chen, L.; Dubowchik, G. M.; Jacutin-Porte, S. E.; Vrudhula, V. M.; Pan, S.; Sivaprakasam, P.; Macor, J. E. (Bristol-Myers Squibb Co.). GSK-3 Inhibitors. International Patent WO 201569594 A1, 2015.
  There is no corresponding record for this reference.
339. 339
  Heuer, T. S.; Oslob, J. D.; Mcdowell, R. S.; Johnson, R.; Yang, H.; Evanchik, M.; Zaharia, C. A.; Cai, H.; Hu, L. W.; Duke, G.; Ohol, Y.; O’Farrell, M. (3-V Biosciences Inc.). Heterocyclic Modulators of Lipid Synthesis and Combinations Thereof. International Patent WO 201595767 A1, 2015.
  There is no corresponding record for this reference.
340. 340
  Albert, R.; Zecri, F.; Cooke, N. G.; Lewis, I. (Novartis AG). Phenyl-Oxetanyl-Derivatives. International Patent WO 2009068682 A2, 2009.
  There is no corresponding record for this reference.
341. 341
  Burger, M.; Ding, Y.; Han, W.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Smith, A. R.; Tamez, Jr., V.; Tanner, H.; Wan, L., (Novartis AG). Tetrasubstituted Cyclohexyl Compounds as Kinase Inhibitors. U.S. Patent US 2012225061 A1, 2012.
  There is no corresponding record for this reference.
342. 342
  Burger, M.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Tamez, Jr., V.; Tanner, H.; Wan, L. (Novartis AG). N-(3-Pyridyl)biarylamides as Kinase Inhibitors. International Patent WO 2014033631 A1, 2014.
  There is no corresponding record for this reference.
343. 343
  Aliagas-Martin, I.; Crawford, J.; Lee, W.; Mathieu, S.; Rudolph, J. (F. Hoffmann-La Roche AG). Serine/threonine PAK1 Inhibitors. International Patent WO 2013026914 A1, 2013.
  There is no corresponding record for this reference.
344. 344
  Estrada, A. A.; Shore, D. G.; Blackwood, E.; Chen, Y.-H.; Deshmukh, G.; Ding, X.; DiPasquale, A. G.; Epler, J. A.; Friedman, L. S.; Koehler, M. F. T. Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR) J. Med. Chem. 2013, 56, 3090– 3101 DOI: 10.1021/jm400194n
  344
  Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)
  Estrada, Anthony A.; Shore, Daniel G.; Blackwood, Elizabeth; Chen, Yung-Hsiang; Deshmukh, Gauri; Ding, Xiao; DiPasquale, Antonio G.; Epler, Jennifer A.; Friedman, Lori S.; Koehler, Michael F. T.; Liu, Lichuan; Malek, Shiva; Nonomiya, Jim; Ortwine, Daniel F.; Pei, Zhonghua; Sideris, Steve; St-Jean, Frederic; Trinh, Lan; Truong, Tom; Lyssikatos, Joseph P.
  Journal of Medicinal Chemistry (2013), 56 (7), 3090-3101CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clin. candidate I (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small mol. inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly obsd. with the THQ scaffold, maintain or improve aq. soly. and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of II (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.
345. 345
  Bowers, S.; Truong, A. P.; Ye, M.; Aubele, D. L.; Sealy, J. M.; Neitz, R. J.; Hom, R. K.; Chan, W.; Dappen, M. S.; Galemmo, R. A. Design and Synthesis of Highly Selective, Orally Active Polo-like Kinase-2 (Plk-2) Inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 2743– 2749 DOI: 10.1016/j.bmcl.2013.02.065
  There is no corresponding record for this reference.
346. 346
  Kinoshita, K.; Ono, Y.; Emura, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Tanaka, S.; Morikami, K.; Tsukaguchi, T. Discovery of Novel Tetracyclic Compounds as Anaplastic Lymphoma Kinase Inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 3788– 3793 DOI: 10.1016/j.bmcl.2011.04.020
  346
  Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors
  Kinoshita, Kazutomo; Ono, Yoshiyuki; Emura, Takashi; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Tanaka, Shota; Morikami, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, Nobuhiro
  Bioorganic & Medicinal Chemistry Letters (2011), 21 (12), 3788-3793CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivs. as potent ALK inhibitors. Among them, compd. 27 showed strong cytotoxicity against KARPAS-299 with an IC50 value of 21 nM and significant antitumor efficacy in ALK fusion-pos. blood and solid cancer xenograft models in mice without body wt. loss.
347. 347
  Kinoshita, K.; Kobayashi, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Hattori, K.; Miyagi, T. 9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors J. Med. Chem. 2011, 54, 6286– 6294 DOI: 10.1021/jm200652u
  347
  9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors
  Kinoshita, Kazutomo; Kobayashi, Takamitsu; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Hara, Sousuke; Ohwada, Jun; Hattori, Kazuo; Miyagi, Takuho; Hong, Woo-Sang; Park, Min-Jeong; Takanashi, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, Nobuhiro
  Journal of Medicinal Chemistry (2011), 54 (18), 6286-6294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E0 region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compd. 13d (I) showed highly selective and potent inhibitory activity against ALK with an IC50 value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC50 value of 12.8 nM. The compd. also displayed significant antitumor efficacy in an established ALK fusion gene-pos. anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body wt. loss.
348. 348
  Song, Z.; Yang, Y.; Liu, Z.; Peng, X.; Guo, J.; Yang, X.; Wu, K.; Ai, J.; Ding, J.; Geng, M.; Zhang, A. Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases J. Med. Chem. 2015, 58, 197– 211 DOI: 10.1021/jm5005144
  There is no corresponding record for this reference.
349. 349
  Phillips, D. P.; Gao, W.; Yang, Y.; Zhang, G.; Lerario, I. K.; Lau, T. L.; Jiang, J.; Wang, X.; Nguyen, D. G.; Bhat, B. G. Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy J. Med. Chem. 2014, 57, 3263– 3282 DOI: 10.1021/jm401731q
  There is no corresponding record for this reference.
350. 350
  Hamzik, P. J.; Brubaker, J. D. Reactions of Oxetan-3-tert-Butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes Org. Lett. 2010, 12, 1116– 1119 DOI: 10.1021/ol100119e
  350
  Reactions of Oxetan-3-tert-butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes
  Hamzik, Philip J.; Brubaker, Jason D.
  Organic Letters (2010), 12 (5), 1116-1119CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The oxetane ring is useful in drug discovery as a bioisostere for both the geminal di-Me group and the carbonyl group. A convenient, straightforward approach to access structurally diverse 3-aminooxetanes through the reactivity of oxetan-3-tert-butylsulfinimine and the corresponding sulfinylaziridine is described. E.g., 1,2-addn. of oxetan-3-tert-butylsulfinimine (I) with PhLi, generated from BuLi and PhBr, gave 91% 3-aminooxetane II.
351. 351
  Jung, H. H.; Buesking, A. W.; Ellman, J. A. Highly Functional Group Compatible Rh-Catalyzed Addition of Arylboroxines to Activated N-tert-Butanesulfinyl Ketimines Org. Lett. 2011, 13, 3912– 3915 DOI: 10.1021/ol201438k
  351
  Highly Functional Group Compatible Rh-Catalyzed Addition of Arylboroxines to Activated N-tert-Butanesulfinyl Ketimines
  Jung, Hyung Hoon; Buesking, Andrew W.; Ellman, Jonathan A.
  Organic Letters (2011), 13 (15), 3912-3915CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The rhodium-catalyzed addn. of readily accessible arylboroxines to N-tert-butanesulfinyl ketimines derived from oxetan-3-one, N-Boc-azetidin-3-one, and isatins proceeds in high yields with excellent functional group compatibility to yield amino oxetanes, amino azetidines, and aminooxindoles tertiary carbinamines, e.g., I. Moreover, high diastereoselectivities are obsd. for the addns. to the N-sulfinyl ketimines derived from isatins.
352. 352
  Brady, P. B.; Carreira, E. M. Addition of Trifluoroborates to Oxetanyl N,O-Acetals: Entry into Spiro and Fused Saturated Heterocycles Org. Lett. 2015, 17, 3350– 3353 DOI: 10.1021/acs.orglett.5b01607
  352
  Addition of Trifluoroborates to Oxetanyl N,O-Acetals: Entry into Spiro and Fused Saturated Heterocycles
  Brady, Patrick B.; Carreira, Erick M.
  Organic Letters (2015), 17 (13), 3350-3353CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  N,O-Acetals derived from 3-oxetanone and 1,2-amino alcs. such as I underwent addn. reactions with alkynyl-, allyl-, allenyl-, and vinylpotassium trifluoroborates such as RC≡CBF3-K+ [R = H, Ph, 4-ClC6H4, 4-MeOC6H4, 3-FC6H4, Me3Si, cyclohexyl, Cl(CH2)3, TBDMSO(CH2)3, PhCH2CH2] to give substituted oxetanamines such as II (R = H, Ph, PhCH2CH2). The oxetanamines underwent ring expansion reactions to give morpholines and fused morpholines such as III and IV [R1 = H, Ph, 4-ClC6H4, Me3Si, cyclohexyl, Cl(CH2)3]. IV (R1 = H, Ph, 4-ClC6H4, Me3Si, cyclohexyl) underwent gold-catalyzed hydroalkoxylation to yield spirofuranbenzooxazines V as the major products. The structures of a hydroxyphenyl (chloropentynyl)oxetanamine and of V (R = 4-ClC6H4) were detd. by X-ray crystallog.
353. 353
  Laporte, R.; Prunier, A.; Pfund, E.; Roy, V.; Agrofoglio, L. A.; Lequeux, T. Synthesis of Fluorine-Containing 3,3-Disubstituted Oxetanes and Alkylidene Oxetanes Eur. J. Org. Chem. 2015, 2015 (14) 3121– 3128 DOI: 10.1002/ejoc.201500172
  There is no corresponding record for this reference.
354. 354
  Hirsch, A. K. H.; Alphey, M. S.; Lauw, S.; Seet, M.; Barandun, L.; Eisenreich, W.; Rohdich, F.; Hunter, W. N.; Bacher, A.; Diederich, F. Inhibitors of the kinase IspE: Structure-activity Relationships and Co-crystal Structure Analysis Org. Biomol. Chem. 2008, 6, 2719– 2730 DOI: 10.1039/b804375b
  There is no corresponding record for this reference.
355. 355
  Phelan, J. P.; Patel, E. J.; Ellman, J. A. Catalytic Enantioselective Addition of Thioacids to Trisubstituted Nitroalkenes Angew. Chem., Int. Ed. 2014, 53, 11329– 11332 DOI: 10.1002/anie.201406971
  355
  Catalytic Enantioselective Addition of Thioacids to Trisubstituted Nitroalkenes
  Phelan, James P.; Patel, Evan J.; Ellman, Jonathan A.
  Angewandte Chemie, International Edition (2014), 53 (42), 11329-11332CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first example of a catalytic enantioselective addn. to and nitronate protonation of trisubstituted nitroalkenes R1R2C:CR3NO2 [R1 = R2 = Me; R1R2 = CH2OCH2, CH2NBocCH2, CH2CH2OCH2CH2, (CH2)5; R3 = Me, Et, i-Pr, PhCH2, MeO2CCH2CH2] to produce highly enantioenriched products R4C(O)SCR1R2CHR3NO2 (R4 = Me, Ph) with a tetrasubstituted carbon is reported. Thioacids R4C(O)SH added in excellent yields and with high enantioselectivities to both activated and unactivated nitroalkenes. The 1,2-nitrothioacetate products can be readily converted in two steps to biomedically relevant 1,2-aminosulfonic acids without loss of enantiopurity.
356. 356
  Phelan, J. P.; Ellman, J. A. Catalytic Enantioselective Addition of Pyrazol-5-Ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst Adv. Synth. Catal. 2016, 358, 1713– 1718 DOI: 10.1002/adsc.201600110
  356
  Catalytic Enantioselective Addition of Pyrazol-5-ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst
  Phelan, James P.; Ellman, Jonathan A.
  Advanced Synthesis & Catalysis (2016), 358 (11), 1713-1718CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first example of enantioselective nitronate protonation following Michael addn. of a carbon nucleophile to an α,β,β-trisubstituted nitroalkene is reported. An N-sulfinylurea catalyst was employed to catalyze the addn. of a variety of 3-substituted pyrazol-5-one nucleophiles to trisubstituted nitroalkenes incorporating an oxetane or azetidine ring at the β-position. The nitroalkane-pyrazolone adducts I (R1 = t-Bu, cyclohexyl, 2,6-Me2C6H3; R2 = H, Me, Et, i-Pr, Ph, (CH2)2OMe; R3 = Et, Me, PhCH2, (CH2)2CO2Me; X = O, N-Boc, N-Cbz, N-Ts) were obtained with good yield and enantioselectivity. Furthermore, the Michael addn. products can be reduced to the corresponding enantioenriched amines with minimal loss of enantiomeric purity.
357. 357
  McLaughlin, M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M. Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry Org. Lett. 2014, 16, 4070– 4073 DOI: 10.1021/ol501590n
  357
  Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry
  McLaughlin, Martin; Yazaki, Ryo; Fessard, Thomas C.; Carreira, Erick M.
  Organic Letters (2014), 16 (16), 4070-4073CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.
358. 358
  Powell, N. H.; Clarkson, G. J.; Notman, R.; Raubo, P.; Martin, N. G.; Shipman, M. Synthesis and Structure of Oxetane Containing Tripeptide Motifs Chem. Commun. 2014, 50, 8797– 8800 DOI: 10.1039/C4CC03507K
  358
  Synthesis and structure of oxetane containing tripeptide motifs
  Powell, Nicola H.; Clarkson, Guy J.; Notman, Rebecca; Raubo, Piotr; Martin, Nathaniel G.; Shipman, Michael
  Chemical Communications (Cambridge, United Kingdom) (2014), 50 (63), 8797-8800CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A new class of peptidomimetic is reported in which one of the amide C:O bonds of the peptide backbone is replaced by an oxetane ring. They are synthesized by conjugate addn. of various α-amino esters to a 3-(nitromethylene)oxetane, redn. of the nitro group and further coupling with N-Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and mol. dynamics simulations.
359. 359
  Beadle, J. D.; Powell, N. H.; Raubo, P.; Clarkson, G. J.; Shipman, M. Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework Synlett 2016, 27, 169– 172 DOI: 10.1055/s-0035-1560593
  There is no corresponding record for this reference.
360. 360
  Monleón, A.; Glaus, F.; Vergura, S.; Jørgensen, K. A. Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds Angew. Chem., Int. Ed. 2016, 55, 2478– 2482 DOI: 10.1002/anie.201510731
  360
  Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds
  Monleon, Alicia; Glaus, Florian; Vergura, Stefania; Jorgensen, Karl Anker
  Angewandte Chemie, International Edition (2016), 55 (7), 2478-2482CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first catalytic enantioselective cycloaddn. reaction to α,β,β-trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodol. provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms, e. g., I, in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and -azetidines. Addnl., the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane.
361. 361
  Beasley, B. O.; Clarkson, G. J.; Shipman, M. Passerini Reactions for the Efficient Synthesis of 3,3-Disubstituted Oxetanes Tetrahedron Lett. 2012, 53, 2951– 2953 DOI: 10.1016/j.tetlet.2012.03.065
  There is no corresponding record for this reference.
362. 362
  Beasley, B. O.; Alli-Balogun, A.; Clarkson, G. J.; Shipman, M. Pictet–Spengler Reactions of Oxetan-3-ones and Related Heterocycles Tetrahedron Lett. 2014, 55, 541– 543 DOI: 10.1016/j.tetlet.2013.11.077
  There is no corresponding record for this reference.
363. 363
  Nassoy, A.-C.; Raubo, P.; Harrity, J. P. A. Synthesis and Cycloaddition Chemistry of Oxetanyl-Substituted Sydnones Tetrahedron Lett. 2013, 54, 3094– 3096 DOI: 10.1016/j.tetlet.2013.03.139
  There is no corresponding record for this reference.
364. 364
  Vo, C.-V. T.; Mikutis, G.; Bode, J. W. SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines—An Alternative to Cross-Coupling with Saturated Heterocycles Angew. Chem., Int. Ed. 2013, 52, 1705– 1708 DOI: 10.1002/anie.201208064
  364
  SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines-An Alternative to Cross-Coupling with Saturated Heterocycles
  Vo, Cam-Van T.; Mikutis, Gediminas; Bode, Jeffrey W.
  Angewandte Chemie, International Edition (2013), 52 (6), 1705-1708CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  We disclose SnAP reagents for the facile conversion of aldehydes into N-unprotected 3-thiomorpholines. This strategy has the potential to be a general approach to installing satd. heterocycles using aldehydes as a synthetic handle. Its successful execution relies on the use of radical chem. to overcome a long-standing challenge in org. synthesis: C-C bond-forming addn. to unactivated primary imines.
365. 365
  Siau, W.-Y.; Bode, J. W. One-Step Synthesis of Saturated Spirocyclic N-Heterocycles with Stannyl Amine Protocol (SnAP) Reagents and Ketones J. Am. Chem. Soc. 2014, 136, 17726– 17729 DOI: 10.1021/ja511232b
  365
  One-Step Synthesis of Saturated Spirocyclic N-Heterocycles with Stannyl Amine Protocol (SnAP) Reagents and Ketones
  Siau, Woon-Yew; Bode, Jeffrey W.
  Journal of the American Chemical Society (2014), 136 (51), 17726-17729CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The combination of cyclic ketones and stannyl amine protocol (SnAP) reagents affords satd., spirocyclic N-heterocycles under operationally simple reaction conditions. The resulting, N-unprotected spirocyclic amines are in great demand as scaffolds for drug discovery and development. The union of SnAP reagents and acyclic trifluoromethyl ketones yields α-CF3 morpholines and piperazines.
366. 366
  Dobi, Z.; Holczbauer, T.; Soós, T. Strain-Driven Direct Cross-Aldol and -Ketol Reactions of Four-Membered Heterocyclic Ketones Org. Lett. 2015, 17, 2634– 2637 DOI: 10.1021/acs.orglett.5b01002
  There is no corresponding record for this reference.
367. 367
  González-Bobes, F.; Fu, G. C. Amino Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with Arylboronic Acids J. Am. Chem. Soc. 2006, 128, 5360– 5361 DOI: 10.1021/ja0613761
  367
  Amino Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with Arylboronic Acids
  Gonzalez-Bobes, Francisco; Fu, Gregory C.
  Journal of the American Chemical Society (2006), 128 (16), 5360-5361CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Suzuki cross-coupling reactions of an unprecedented array of un-activated primary and secondary alkyl halides (including challenging alkyl chlorides) can be accomplished through the use of nickel/amino alc.-based catalysts. Both the nickel pre-catalyst and the amino alcs. (prolinol or trans-2-aminocyclohexanol) are com. available and air-stable. In view of the remarkable diversity of amino alcs. that are readily accessible, this discovery may open the door to the rapid development of versatile catalysts for a wide range of cross-coupling processes.
368. 368
  Zhang, X.; Yang, C. Alkylations of Arylboronic Acids including Difluoroethylation/Trifluoroethylation via Nickel-Catalyzed Suzuki Cross-Coupling Reaction Adv. Synth. Catal. 2015, 357, 2721– 2727 DOI: 10.1002/adsc.201500346
  368
  Alkylations of Arylboronic Acids including Difluoroethylation/Trifluoroethylation via Nickel-Catalyzed Suzuki Cross-Coupling Reaction
  Zhang, Xiaofei; Yang, Chunhao
  Advanced Synthesis & Catalysis (2015), 357 (12), 2721-2727CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An efficient alkylation method of functionalized alkyl halides under mild nickel-catalyzed C(sp3) - C(sp2) Suzuki cross-coupling conditions was described. The features of this approach are excellent functional group compatibility, low cost nickel catalyst, and the use of a mild base. This is also the first successful example of the nickel-catalyzed direct 2,2-difluoroethylation or 2,2,2-trifluoroethylation of aryl-/heteroarylboronic acids.
369. 369
  Duncton, M. A. J.; Estiarte, M. A.; Johnson, R. J.; Cox, M.; O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. Preparation of Heteroaryloxetanes and Heteroarylazetidines by Use of a Minisci Reaction J. Org. Chem. 2009, 74, 6354– 6357 DOI: 10.1021/jo9010624
  369
  Preparation of Heteroaryloxetanes and Heteroarylazetidines by Use of a Minisci Reaction
  Duncton, Matthew A. J.; Estiarte, M. Angels; Johnson, Russell J.; Cox, Matthew; O'Mahony, Donogh J. R.; Edwards, William T.; Kelly, Michael G.
  Journal of Organic Chemistry (2009), 74 (16), 6354-6357CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroarom. bases was achieved by using a radical addn. method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetidine into heteroarom. systems that have found important uses in the drug discovery industry, such as the marketed EGFR inhibitor gefitinib, a quinolinecarbonitrile Src tyrosine kinase inhibitor, and the antimalarial hydroquinine.
370. 370
  Presset, M.; Fleury-Brégeot, N.; Oehlrich, D.; Rombouts, F.; Molander, G. A. Synthesis and Minisci Reactions of Organotrifluoroborato Building Blocks J. Org. Chem. 2013, 78, 4615– 4619 DOI: 10.1021/jo4005519
  370
  Synthesis and Minisci Reactions of Organotrifluoroborato Building Blocks
  Presset, Marc; Fleury-Bregeot, Nicolas; Oehlrich, Daniel; Rombouts, Frederik; Molander, Gary A.
  Journal of Organic Chemistry (2013), 78 (9), 4615-4619CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Copper-catalyzed borylation of a variety of org. halides with bis(pinacolato)diboron allows the prepn. of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-contg. building blocks, including those contg. piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are reported for select examples.
371. 371
  Molander, G. A.; Traister, K. M.; O’Neill, B. T. Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and Heteroaryl Bromides J. Org. Chem. 2014, 79, 5771– 5780 DOI: 10.1021/jo500905m
  371
  Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and Heteroaryl Bromides
  Molander, Gary A.; Traister, Kaitlin M.; O'Neill, Brian T.
  Journal of Organic Chemistry (2014), 79 (12), 5771-5780CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Reductive cross-coupling allows the direct C-C bond formation between two org. halides without the need for preformation of an organometallic reagent. A method has been developed for the reductive cross-coupling of nonarom., heterocyclic bromides with aryl or heteroaryl bromides. The developed conditions use an air-stable Ni(II) source in the presence of a diamine ligand and a metal reductant to allow late-stage incorporation of satd. heterocyclic rings onto aryl halides in a functional-group tolerant manner. E.g., in presence of NiCl2.(glyme), 1,10-phenanthroline, 4-ethylpyridine, NaBF4, and Mn in MeOH, cross-coupling of 3-bromotetrahydrofuran and 4-BrC6H4COMe gave 54% I.
372. 372
  Bhonde, V. R.; O’Neill, B. T.; Buchwald, S. L. An Improved System for the Aqueous Lipshutz-Negishi Cross-Coupling of Alkyl Halides with Aryl Electrophiles Angew. Chem., Int. Ed. 2016, 55, 1849– 1853 DOI: 10.1002/anie.201509341
  372
  An improved system for the aqueous Lipshutz-Negishi cross-coupling of alkyl halides with aryl electrophiles
  Bhonde, Vasudev R.; O'Neill, Brian T.; Buchwald, Stephen L.
  Angewandte Chemie, International Edition (2016), 55 (5), 1849-1853CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.
373. 373
  Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids J. Org. Chem. 2014, 79, 328– 338 DOI: 10.1021/jo402526z
  373
  Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids
  Allwood, Daniel M.; Blakemore, David C.; Brown, Alan D.; Ley, Steven V.
  Journal of Organic Chemistry (2014), 79 (1), 328-338CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The coupling of arom. moieties with satd. heterocyclic partners is currently an area of significant interest for the pharmaceutical industry. Herein, we present a procedure for the metal-free coupling of 4-, 5-, and 6-membered satd. heterocyclic p-methoxyphenyl (PMP) sulfonylhydrazones with aryl and heteroarom. boronic acids. This procedure enables a simple, two-step synthesis of a range of functionalized sp2-sp3 linked bicyclic building blocks, including oxetanes, piperidines, and azetidines, from their parent ketones.
374. 374
  Nassoy, A.-C. M. A.; Raubo, P.; Harrity, J. P. A. Synthesis and Indole Coupling Reactions of Azetidine and Oxetane Sulfinate Salts Chem. Commun. 2015, 51, 5914– 5916 DOI: 10.1039/C5CC00975H
  There is no corresponding record for this reference.
375. 375
  Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Brown, H. S.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Leach, A. G.; MacFaul, P. A.; McKerrecher, D. Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists MedChemComm 2013, 4, 95– 100 DOI: 10.1039/C2MD20130E
  There is no corresponding record for this reference.
376. 376
  Pei, Z.; Blackwood, E.; Liu, L.; Malek, S.; Belvin, M.; Koehler, M. F. T.; Ortwine, D. F.; Chen, H.; Cohen, F.; Kenny, J. R. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349 ACS Med. Chem. Lett. 2013, 4, 103– 107 DOI: 10.1021/ml3003132
  376
  Discovery and biological profiling of potent and selective mTOR inhibitor GDC-0349
  Pei, Zhonghua; Blackwood, Elizabeth; Liu, Lichuan; Malek, Shiva; Belvin, Marcia; Koehler, Michael F. T.; Ortwine, Daniel F.; Chen, Huifen; Cohen, Frederick; Kenny, Jane R.; Bergeron, Philippe; Lau, Kevin; Ly, Cuong; Zhao, Xianrui; Estrada, Anthony A.; Truong, Tom; Epler, Jennifer A.; Nonomiya, Jim; Trinh, Lan; Sideris, Steve; Lesnick, John; Bao, Linda; Vijapurkar, Ulka; Mukadam, Sophie; Tay, Suzanne; Deshmukh, Gauri; Chen, Yung-Hsiang; Ding, Xiao; Friedman, Lori S.; Lyssikatos, Joseph P.
  ACS Medicinal Chemistry Letters (2013), 4 (1), 103-107CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been obsd. in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead I(R = H, Me) culminated in the discovery of clin. development candidate II, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.
377. 377
  Jadhav, P. K.; Schiffler, M. A.; Gavardinas, K.; Kim, E. J.; Matthews, D. P.; Staszak, M. A.; Coffey, D. S.; Shaw, B. W.; Cassidy, K. C.; Brier, R. A. Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm ACS Med. Chem. Lett. 2014, 5, 1138– 1142 DOI: 10.1021/ml500283g
  There is no corresponding record for this reference.
378. 378
  Schoenfeld, R. C.; Bourdet, D. L.; Brameld, K. A.; Chin, E.; de Vicente, J.; Fung, A.; Harris, S. F.; Lee, E. K.; Le Pogam, S.; Leveque, V. Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B J. Med. Chem. 2013, 56, 8163– 8182 DOI: 10.1021/jm401266k
  378
  Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B
  Schoenfeld, Ryan C.; Bourdet, David L.; Brameld, Ken A.; Chin, Elbert; de Vicente, Javier; Fung, Amy; Harris, Seth F.; Lee, Eun K.; Le Pogam, Sophie; Leveque, Vincent; Li, Jim; Lui, Alfred S.-T.; Najera, Isabel; Rajyaguru, Sonal; Sangi, Michael; Steiner, Sandra; Talamas, Francisco X.; Taygerly, Joshua P.; Zhao, Junping
  Journal of Medicinal Chemistry (2013), 56 (20), 8163-8182CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Hepatitis C virus (HCV) is a major global public health problem. While the current std. of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed to provide a clin. candidate in fluoropyridone (I).
379. 379
  Gonzalez, A. Z.; Eksterowicz, J.; Bartberger, M. D.; Beck, H. P.; Canon, J.; Chen, A.; Chow, D.; Duquette, J.; Fox, B. M.; Fu, J. Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction J. Med. Chem. 2014, 57, 2472– 2488 DOI: 10.1021/jm401767k
  379
  Selective and Potent Morpholinone Inhibitors of the MDM2-p53 Protein-Protein Interaction
  Gonzalez, Ana Z.; Eksterowicz, John; Bartberger, Michael D.; Beck, Hilary P.; Canon, Jude; Chen, Ada; Chow, David; Duquette, Jason; Fox, Brian M.; Fu, Jiasheng; Huang, Xin; Houze, Jonathan B.; Jin, Lixia; Li, Yihong; Li, Zhihong; Ling, Yun; Lo, Mei-Chu; Long, Alexander M.; McGee, Lawrence R.; McIntosh, Joel; McMinn, Dustin L.; Oliner, Jonathan D.; Osgood, Tao; Rew, Yosup; Saiki, Anne Y.; Shaffer, Paul; Wortman, Sarah; Yakowec, Peter; Yan, Xuelei; Ye, Qiuping; Yu, Dongyin; Zhao, Xiaoning; Zhou, Jing; Olson, Steven H.; Medina, Julio C.; Sun, Daqing
  Journal of Medicinal Chemistry (2014), 57 (6), 2472-2488CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogs led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 (I) emerged as an inhibitor with remarkable biochem. potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. I also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
380. 380
  Austin, W. F.; Hubbs, J. L.; Fuller, N. O.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M. B.; Findeis, M. A.; Tate, B.; Ives, J. L.; Bronk, B. S. SAR Investigations on a Novel Class of Gamma-Secretase Modulators Based on a Unique Scaffold MedChemComm 2013, 4, 569– 574 DOI: 10.1039/c3md20357c
  There is no corresponding record for this reference.
381. 381
  Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M. B.; Tate, B.; Xia, W.; Ives, J. Optimization of a Natural Product-Based Class of γ-Secretase Modulators J. Med. Chem. 2012, 55, 9270– 9282 DOI: 10.1021/jm300976b
  381
  Optimization of a Natural Product-Based Class of γ-Secretase Modulators
  Hubbs, Jed L.; Fuller, Nathan O.; Austin, Wesley F.; Shen, Ruichao; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey; Bronk, Brian S.
  Journal of Medicinal Chemistry (2012), 55 (21), 9270-9282CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compds. with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochem. properties of the analogs. This strategy gave compds. with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compds., I and II, were tested for a pharmacodynamic effect and exhibited statistically significant lowering of brain Aβ42 levels.
382. 382
  Procopiou, P. A.; Barrett, J. W.; Barton, N. P.; Begg, M.; Clapham, D.; Copley, R. C. B.; Ford, A. J.; Graves, R. H.; Hall, D. A.; Hancock, A. P. Synthesis and Structure–Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists J. Med. Chem. 2013, 56, 1946– 1960 DOI: 10.1021/jm301572h
  382
  Synthesis and Structure-Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists
  Procopiou, Panayiotis A.; Barrett, John W.; Barton, Nicholas P.; Begg, Malcolm; Clapham, David; Copley, Royston C. B.; Ford, Alison J.; Graves, Rebecca H.; Hall, David A.; Hancock, Ashley P.; Hill, Alan P.; Hobbs, Heather; Hodgson, Simon T.; Jumeaux, Coline; Lacroix, Yannick M. L.; Miah, Afjal H.; Morriss, Karen M. L.; Needham, Deborah; Sheriff, Emma B.; Slack, Robert J.; Smith, Claire E.; Sollis, Steven L.; Staton, Hugo
  Journal of Medicinal Chemistry (2013), 56 (5), 1946-1960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A series of indazole arylsulfonamides were synthesized and examd. as human CCR4 antagonists. Methoxy- or hydroxyl- contg. groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogs being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]- group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogs, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compd. with high absorption in two species was analog I (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramol. interaction in the active conformation.
383. 383
  Dineen, T. A.; Chen, K.; Cheng, A. C.; Derakhchan, K.; Epstein, O.; Esmay, J.; Hickman, D.; Kreiman, C. E.; Marx, I. E.; Wahl, R. C. Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718) J. Med. Chem. 2014, 57, 9811– 9831 DOI: 10.1021/jm5012676
  383
  Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718)
  Dineen, Thomas A.; Chen, Kui; Cheng, Alan C.; Derakhchan, Katayoun; Epstein, Oleg; Esmay, Joel; Hickman, Dean; Kreiman, Chuck E.; Marx, Isaac E.; Wahl, Robert C.; Wen, Paul H.; Weiss, Matthew M.; Whittington, Douglas A.; Wood, Stephen; Fremeau, Robert T.; White, Ryan D.; Patel, Vinod F.
  Journal of Medicinal Chemistry (2014), 57 (23), 9811-9831CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compds. exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compd. with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compd. produced robust and sustained redns. of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
384. 384
  Pierson, P. D.; Fettes, A.; Freichel, C.; Gatti-McArthur, S.; Hertel, C.; Huwyler, J.; Mohr, P.; Nakagawa, T.; Nettekoven, M.; Plancher, J.-M. 5-Hydroxyindole-2-carboxylic Acid Amides: Novel Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity J. Med. Chem. 2009, 52, 3855– 3868 DOI: 10.1021/jm900409x
  There is no corresponding record for this reference.
385. 385
  Adrian Meredith, J.; Wallberg, H.; Vrang, L.; Oscarson, S.; Parkes, K.; Hallberg, A.; Samuelsson, B. Design and Synthesis of Novel P2 Substituents in Diol-Based HIV Protease Inhibitors Eur. J. Med. Chem. 2010, 45, 160– 170 DOI: 10.1016/j.ejmech.2009.09.038
  There is no corresponding record for this reference.
386. 386
  Oscarsson, K.; Classon, B.; Kvarnström, I.; Hallberg, A.; Samuelsson, B. Solid Phase Assisted Synthesis of HIV-1 Protease Inhibitors. Expedient Entry to Unsymmetrical Substitution of a C2 Symmetric Template Can. J. Chem. 2000, 78, 829– 837 DOI: 10.1139/v00-012
  There is no corresponding record for this reference.
387. 387
  Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, K.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D. The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α J. Med. Chem. 2012, 55, 8007– 8020 DOI: 10.1021/jm300867c
  387
  The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α
  Heffron, Timothy P.; Salphati, Laurent; Alicke, Bruno; Cheong, Jonathan; Dotson, Jennafer; Edgar, Kyle; Goldsmith, Richard; Gould, Stephen E.; Lee, Leslie B.; Lesnick, John D.; Lewis, Cristina; Ndubaku, Chudi; Nonomiya, Jim; Olivero, Alan G.; Pang, Jodie; Plise, Emile G.; Sideris, Steve; Trapp, Sean; Wallin, Jeffrey; Wang, Lan; Zhang, Xiaolin
  Journal of Medicinal Chemistry (2012), 55 (18), 8007-8020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, the authors report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. The authors leveraged the authors' historical experience with PI3K inhibitors to identify correlations between physicochem. properties and transporter efflux as well as metabolic stability to focus the selection of mols. for further study.
388. 388
  Patel, S.; Cohen, F.; Dean, B. J.; De La Torre, K.; Deshmukh, G.; Estrada, A. A.; Ghosh, A. S.; Gibbons, P.; Gustafson, A.; Huestis, M. P. Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models J. Med. Chem. 2015, 58, 401– 418 DOI: 10.1021/jm5013984
  388
  Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models
  Patel, Snahel; Cohen, Frederick; Dean, Brian J.; De La Torre, Kelly; Deshmukh, Gauri; Estrada, Anthony A.; Ghosh, Arundhati Sengupta; Gibbons, Paul; Gustafson, Amy; Huestis, Malcolm P.; Le Pichon, Claire E.; Lin, Han; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Ly, Cuong Q.; Lyssikatos, Joseph P.; Ma, Changyou; Scearce-Levie, Kimberly; Shin, Young G.; Solanoy, Hilda; Stark, Kimberly L.; Wang, Jian; Wang, Bei; Zhao, Xianrui; Lewcock, Joseph W.; Siu, Michael
  Journal of Medicinal Chemistry (2015), 58 (1), 401-418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here the authors describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike mols., the authors came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. The lead inhibitor GNE-3511 I displayed concn.-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacol. inhibition of DLK may have therapeutic potential in multiple indications.
389. 389
  Chen, L.; Feng, L.; Feng, S.; Gao, L.; Guo, T.; Huang, M.; Liang, C.; Liu, Y.; Wang, L.; Wong, J. C. (F. Hoffmann-La Roche AG). Preparation of Benzothiazepines and Analogs for the Treatment and Prophylaxis of Respiratory Syncytial Virus Infection. International Patent WO 2013020993 A1, 2013.
  There is no corresponding record for this reference.
390. 390
  Chen, J.; Ren, Y.; She, J.; Wang, L.; Yu, J.; Zhang, G. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Process for the Preparation of N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methylquinazolin-4-amine. International Patent WO 2015110446 A1, 2015.
  There is no corresponding record for this reference.
391. 391
  Rosenberg, S. H. (Abbott Laboratories). Preparation of Oxiranyl and Oxetanyl Renin Inhibiting Compounds. International Patent WO 9222313 A1, 1992.
  There is no corresponding record for this reference.
392. 392
  Bhatnagar, P. K.; Hartmann, M.; Hiebl, J.; Kremminger, P.; Rovenszky, F. (SmithKline Beecham Corp.; Nycomed Austria GmbH). Pharmaceutical Compositions Containing Substituted Alkylenebisamides for Hemoregulation. International Patent WO 9717964 A1, 1997.
  There is no corresponding record for this reference.
393. 393
  Ndakala, A. J.; Howell, A. R. The First General Synthesis of 1,5-Dioxaspiro Hexanes J. Org. Chem. 1998, 63, 6098– 6099 DOI: 10.1021/jo981309s
  There is no corresponding record for this reference.
394. 394
  Howell, A.; Taboada, R.; Richardson, S. (University of Connecticut). Preparation of Heterocyclyl-Substituted Oxetanes for the Treatment of Proliferative or Infectious Diseases. International Patent WO 2005051944 A1, 2005.
  There is no corresponding record for this reference.
395. 395
  Malamas, M. S.; Erdei, J. J.; Gunawan, I. S.; Barnes, K. D.; Johnson, M. R.; Hui, Y. (Wyeth, John, and Brother Ltd.). Preparation of Diphenylimidazopyrimidine and -Imidazole Amines as Selective Inhibitors of B-Secretase for Use against Alzheimer’s Disease and Other Disorders. U.S. Patent US 20050282826 A1, 2005.
  There is no corresponding record for this reference.
396. 396
  Brodney, M. A. (Pfizer Products Inc.). Preparation of Pyridyl-Lactams as 5-HT1 Receptors Ligands. International Patent WO 2006106416 A1, 2006.
  There is no corresponding record for this reference.
397. 397
  Berthel, S. J.; Kester, R. F.; Murphy, D. E.; Prins, T. J.; Ruebsam, F.; Sarabu, R.; Tran, C. V.; Vourloumis, D. (Hoffmann-La Roche Inc.). Preparation of Pyrazole Derivatives as Glucokinase Activators. U.S. Patent US 20080021032 A1, 2008.
  There is no corresponding record for this reference.
398. 398
  Felding, J.; Nielsen, S. F.; Larsen, J. C. H.; Babu, B. R. (Leo Pharma A/S). Preparation of Spirobenzodioxoles and Spirobenzodioxepins as Phosphodiesterase PDE4 Inhibitors. International Patent WO 2008104175 A2, 2008; .
  There is no corresponding record for this reference.
399. 399
  Ahrendt, K. A.; Buckmelter, A. J.; De Meese, J.; Grina, J.; Hansen, J. D.; Laird, E. R.; Lunghofer, P.; Moreno, D.; Newhouse, B.; Ren, L. (Array BioPharma Inc.; Genentech, Inc.). N-Pyrazolo[3,4-b]pyridinyl Benzamide Derivatives as Raf Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Diseases. International Patent WO 2009111279 A1, 2009.
  There is no corresponding record for this reference.
400. 400
  Labadie, S. S.; Lin, C. J. J.; Talamas, F. X.; Weikert, R. J. (F. Hoffmann-La Roche AG). Benzofuran-3-carboxamide Derivatives and Their Pharmaceutical Compositions as Antiviral Agents Useful in the Treatment of Hepatitis C Infection and Preparation Thereof. International Patent WO 2009101022 A1, 2009.
  There is no corresponding record for this reference.
401. 401
  Chen, L.; Firooznia, F.; Gillespie, P.; He, Y.; Lin, T.-A.; Mertz, E.; So, S.-S.; Yun, H.; Zhang, Z. (F. Hoffmann-La Roche AG). Preparation of Naphthylacetic Acids as Antagonists or Partial Agonists at the CRTH2 Receptor. International Patent WO 2010055004 A1, 2010.
  There is no corresponding record for this reference.
402. 402
  Fessard, T.; Li, D.-B.; Barbaras, D.; Wolfrum, S.; Carreira, E. (Lipideon Biotechnology AG). Preparation of Azetidinone-Containing Compounds for Pharmaceutical Hypocholesterolemic Compositions. International Patent WO 2010100255 A1, 2010.
  There is no corresponding record for this reference.
403. 403
  Bleicher, K.; Flohr, A.; Groebke Zbinden, K.; Gruber, F.; Koerner, M.; Kuhn, B.; Peters, J.-U.; Rodriguez Sarmiento, R. M. (F. Hoffmann-La Roche AG). Nitrogen-Containing Heteroaryl Compounds as PDE10A Inhibitors and Their Preparation and Use in the Treatment of Diseases. International Patent WO 2011154327 A1, 2011.
  There is no corresponding record for this reference.
404. 404
  Boys, M. L.; Burgess, L. E.; Groneberg, R. D.; Harvey, D. M.; Huang, L.; Kercher, T.; Kraser, C. F.; Laird, E.; Tarlton, E.; Zhao, Q. (Array BioPharma Inc.). Imidazo[1,2-c]pyrimidine Derivatives as JAK Inhibitors and Their Preparation and Use for the Treatment of Autoimmune and Inflammatory Diseases. International Patent WO 2011130146 A1, 2011.
  There is no corresponding record for this reference.
405. 405
  Nielsen, S. F.; Horneman, A. M.; Lau, J. F.; Larsen, J. C. H. (Leo Pharma A/S). Biaryl Derivatives as Phosphodiesterase Inhibitors and Their Preparation and Use in the Treatment of Diseases. International Patent WO 2011134468 A1, 2011.
  There is no corresponding record for this reference.
406. 406
  Saxty, G.; Murray, C. W.; Berdini, V.; Besong, G. E.; Hamlett, C. C. F.; Johnson, C. N.; Woodhead, S. J.; Reader, M.; Rees, D. C.; Mevellec, L. A., (Astex Therapeutics Ltd.). Preparation of Pyrazolylquinazoline Derivatives for Use as Kinase Inhibitors. International Patent WO 2011135376 A1, 2011.
  There is no corresponding record for this reference.
407. 407
  Young, J.; Czako, B.; Altman, M.; Guerin, D.; Martinez, M.; Rivkin, A.; Wilson, K.; Lipford, K.; White, C.; Surdi, L., (Merck Sharp & Dohme Corp.). Pyridazinones as Tyrosine Kinase Inhibitors and Their Preparation and Use in the Treatment of Cancer. International Patent WO 2011084402 A1, 2011; .
  There is no corresponding record for this reference.
408. 408
  Bissantz, C.; Dehmlow, H.; Erickson, S. D.; Karnachi, P. S.; Kim, K.; Martin, R. E.; Mattei, P.; Obst Sander, U.; Pietranico-Cole, S. L.; Richter, H.; Ullmer, C. (F. Hoffmann-La Roche AG). 3-Aminopyridines as GPBAR1 Agonists and Their Preparation and Use in the Treatment of Type II Diabetes. International Patent WO 2012117000 A1, 2012.
  There is no corresponding record for this reference.
409. 409
  Roth, G. J.; Fleck, M.; Lehmann-Lintz, T.; Neubauer, H.; Nosse, B. (Boehringer Ingelheim International GmbH). Piperidine Derivatives as Acetyl-CoA Carboxylase Inhibitors and Their Preparation and Use for the Treatment of Metabolic Disorders. International Patent WO 2012001107 A1, 2012.
  There is no corresponding record for this reference.
410. 410
  Aciro, C.; Steadman, V. A.; Pettit, S. N.; Poullennec, K. G.; Lazarides, L.; Dean, D. K.; Dunbar, N. A.; Highton, A. J.; Keats, A. J.; Siegel, D. S., (Gilead Sciences, Inc.; Selcia Ltd.). Preparation of Macrocyclic Peptides as Inhibitors of Flaviviridae Viruses. International Patent WO 2013185103 A1, 2013.
  There is no corresponding record for this reference.
411. 411
  Chen, X.-T. (New Hope R & D Bioscience, Inc.). Preparation of Oxetane Dicarboxamide Derivatives for Use as Protein Kinase Activity Modulators. International Patent WO 2013032797 A2, 2013.
  There is no corresponding record for this reference.
412. 412
  Feng, J.; Haynes, N.-E.; Hermann, J. C.; Kim, K.; Liu, J.-J.; Scott, N. R.; Yi, L.; Zak, M.; Zhao, G. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Preparation of Pyrazolopyrimidones and Pyrazolopyridones as Tankyrase Inhibitors. International Patent WO 2013182546 A1, 2013.
  There is no corresponding record for this reference.
413. 413
  Fukuda, Y.; Kaelin, D. E., Jr.; Singh, S. B. (Kyorin Pharmaceutical Co., Ltd.; Merck Sharp & Dohme Corp.). Bridged Bicyclic Compounds as Antibacterial Agents and Their Preparation and Use for the Treatment of Bacterial Infections. International Patent WO 2013003383 A1, 2013.
  There is no corresponding record for this reference.
414. 414
  Gelin, C.; Flyer, A.; Adams, C. M.; Darsigny, V.; Hurley, T. B.; Karki, R. G.; Ji, N.; Kawanami, T.; Meredith, E.; Serrano-Wu, M. H., (Novartis AG). Tetrahydropyridopyridine and Tetrahydropyridopyrimidine Compounds as C5A Receptor Modulators and Their Preparation. International Patent WO 2013016197 A1, 2013.
  There is no corresponding record for this reference.
415. 415
  Hata, S.; Yuki, Y.; Raeppel, F.; Raeppel, S.; Vaisburg, A. (MethylGene Inc.). Preparation of Thienopyridines Useful as PTK Inhibitors in the Treatment of Disease Such as Ophthalmic Disorders. International Patent WO 2013044360 A1, 2013.
  There is no corresponding record for this reference.
416. 416
  Hodges, A. J.; Matteucci, M.; Sharpe, A.; Sun, M.; Wang, X.; Tsui, V. H. (Genentech, Inc.; F. Hoffmann-La Roche AG). Pyrazol-4-yl-heterocyclyl-carboxamide Compounds and Methods of Use. U.S. Patent US 20130079321 A1, 2013.
  There is no corresponding record for this reference.
417. 417
  Houpis, I. N.; Jonckers, T. H. M.; Raboisson, P. J.-M. B.; Tahri, A. (Janssen R&D Ireland). Preparation of Uracil Spiro-oxetane Nucleoside Cyclo-phosphates as Anti-HCV Antiviral Agents. International Patent WO 2013174962 A1, 2013.
  There is no corresponding record for this reference.
418. 418
  Liu, X.; Li, X.; Loren, J.; Molteni, V.; Nabakka, J.; Nguyen, B.; Petrassi, H. M. J.; Yeh, V. (IRM LLC). Imidazopyridine Compounds and Compositions as c-kit Kinase Inhibitors and Their Preparation. International Patent WO 2013033116 A1, 2013.
  There is no corresponding record for this reference.
419. 419
  Michels, P. C.; Khmelnitsky, Y. L.; Gutterman, J.; Haridas, V.; Mozhaev, V. M. (Research Development Foundation). Preparation of Avicin D Derivatives as Antitumor Agents. International Patent WO 2013126730 A1, 2013.
  There is no corresponding record for this reference.
420. 420
  Suzuki, M.; Kondo, K.; Kurimura, M.; Valluru, K. R.; Takahashi, A.; Kuroda, T.; Takahashi, H.; Fukushima, T.; Miyamura, S.; Ghosh, I., (Otsuka Pharmaceutical Co., Ltd.). Quinazolines as STEP Inhibitors and Their Preparation and Use in the Treatment of Central Nervous System Agents. International Patent WO 2013003586 A1, 2013.
  There is no corresponding record for this reference.
421. 421
  Aktoudianakis, E.; Chin, G.; Corkey, B. K.; Du, J.; Elbel, K.; Jiang, R. H.; Kobayashi, T.; Lee, R.; Martinez, R.; Metobo, S. E., (Gilead Sciences, Inc.). Benzimidazole Derivatives as Bromodomain Inhibitors and Their Preparation. International Patent WO 2014182929 A1, 2014.
  There is no corresponding record for this reference.
422. 422
  Amans, D.; Bamborough, P.; Barker, M. D.; Bit, R. A.; Brown, J. A.; Campbell, M.; Garton, N. S.; Lindon, M. J.; Shipley, T. J.; Theodoulou, N. H.; Wellaway, C. R.; Westaway, S. M. (GlaxoSmithKline Intellectual Property No. 2 Ltd.). Preparation of Furopyridines as Bromodomain Inhibitors Useful in Treating Cancer, Inflammation, and Autoimmune Disorders. International Patent WO 2014140077 A1, 2014.
  There is no corresponding record for this reference.
423. 423
  Balestra, M.; Burke, J.; Chen, Z.; Cogan, D.; Fader, L.; Guo, X.; McKibben, B.; Marshall, D. R.; Nemoto, P. A.; Yu, H. (Boehringer Ingelheim International GmbH). Naphthyridines, Azaindoles and Related Compounds as Aldosterone Synthase Inhibitors and Their Preparation. U.S. Patent US 20140323468 A1, 2014.
  There is no corresponding record for this reference.
424. 424
  Baugh, S. D. P.; Ye, H.; Xu, X.; Guo, J.-T.; Xiao, T.; Du, Y.; Block, T. (Drexel; Institute for Hepatitis and Virus Research; Enantigen Therapeutics, Inc.). Preparation of Sulfonamide Substituted Benzamides as Novel Antiviral Agents against HBV Infection. International Patent WO 2014106019 A2, 2014.
  There is no corresponding record for this reference.
425. 425
  Bourque, E.; Cabrera-Salazar, M. A.; Celatka, C.; Cheng, S. H.; Hirth, B.; Good, A.; Jancsics, K.; Marshall, J.; Metz, M.; Scheule, R. K., (Genzyme Corp.). Azabicycles as Glucosylceramide Synthase Inhibitors and Their Preparation. International Patent WO 2014043068 A1, 2014.
  There is no corresponding record for this reference.
426. 426
  Brookfield, F.; Burch, J.; Goldsmith, R. A.; Hu, B.; Lau, K. H. L.; Mackinnon, C. H.; Ortwine, D. F.; Pei, Z.; Wu, G.; Yuen, P.-W.; Zhang, Y. (F. Hoffmann-La Roche AG; Genentech, Inc.). Preparation of N-(1H-Pyrazol-4-yl)-1H-pyrazole-3-arboxamide Compounds as Inhibitors of ITK Kinase. International Patent WO 2014023258 A1, 2014.
  There is no corresponding record for this reference.
427. 427
  Brunner, D.; Hilpert, H.; Kolczewski, S.; Limberg, A.; Malberg, J.; Prinssen, E.; Riemer, C.; Shankar, B. G.; Stoll, T. (F. Hoffmann-La Roche AG; Hoffmann-La Roche Inc.). Preparation of Indolin-2-one or Pyrrolopyridin-2-one and Pyrrolopyrimidin-2-one Derivatives for Treating CNS Diseases. International Patent WO 2014202493 A1, 2014.
  There is no corresponding record for this reference.
428. 428
  Burger, M.; Nishiguchi, G.; Rico, A.; Simmons, R. L.; Tamez, V., Jr.; Tanner, H.; Wan, L. (Novartis AG). N-(3-Pyridyl)biarylamides as Kinase Inhibitors and Their Preparation. International Patent WO 2014033631 A1, 2014.
  There is no corresponding record for this reference.
429. 429
  Chaudhary, D.; Kapeller-Libermann, R. (Nimbus Iris, Inc.). Preparation of Thienopyrimidine-Containing Tricyclic Compounds That Are FLT3 Inhibitors Useful in Treatment of FLT3-Mediated Disorders. International Patent WO 2014194242 A2, 2014.
  There is no corresponding record for this reference.
430. 430
  Dunman, P. M.; Krysan, D. J.; Flaherty, D. P. (University of Rochester; University of Kansas). Substituted Piperidine Derivatives and Their Preparation. Methods and Compositions for Treating Infection. International Patent WO 2014052836 A2, 2014.
  There is no corresponding record for this reference.
431. 431
  Glunz, P. W.; Zou, Y.; Quan, M. L.; Ladziata, V. (Bristol-Myers Squibb Co.). Phthalazinones and Isoquinolinones as ROCK Inhibitors. International Patent WO 2014113620 A2, 2014.
  There is no corresponding record for this reference.
432. 432
  Hynd, G.; Price, S.; Kulagowski, J.; MacLeod, C.; Mann, S. E.; Panchal, T. A.; Tisselli, P.; Montana, J. G. (Janssen Pharmaceutica NV). Preparation of Aminopyrimidinylhydroxypropynylpyrrolopyridine Derivatives for Use as NIK Inhibitors. International Patent WO 2014174021 A1, 2014.
  There is no corresponding record for this reference.
433. 433
  Jantos, K.; Braje, W.; Geneste, H.; Kling, A.; Unger, L.; Behl, B.; Van Gaalen, M.; Hornberger, W.; Laplanche, L.; Weber, S. (Abbvie Deutschland GmbH & Co. KG). Oxindole Derivatives Carrying an Oxetane Substituent Useful in Treating Vasopressine-Related Diseases. International Patent WO 2014140186 A1, 2014.
  There is no corresponding record for this reference.
434. 434
  Wang, T.; Zhang, Z.; Yin, Z.; Sun, L.-Q.; Mull, E.; Zhao, Q.; Scola, P. M. (Bristol-Myers Squibb Co.). Macrocyclic Molecules as HCV Entry Inhibitors and Their Preparation. International Patent WO 2014123894 A1, 2014.
  There is no corresponding record for this reference.
435. 435
  Van Niel, M. B.; Fauber, B.; Gancia, E.; Gaines, S.; Gobbi, A.; Laddywahetty, T.; Rene, O.; Vesey, D.; Ward, S.; Winship, P. (F. Hoffmann-La Roche AG; Genentech, Inc.). Aryl Sultam Derivatives as RORc Modulators and Their Preparation. International Patent WO 2015104356 A1, 2015.
  There is no corresponding record for this reference.
436. 436
  Chapoux, G.; Gauvin, J.-C.; Panchaud, P.; Specklin, J.-L.; Surivet, J.-P.; Schmitt, C. (Actelion Pharmaceuticals Ltd.). Preparation of Dihydropyrrolo[1,2-c]Imidazol-3-One Derivatives Useful as Antibacterial Agents. International Patent WO 2015132228 A1, 2015.
  There is no corresponding record for this reference.
437. 437
  Currie, K. S.; Du, Z.; Farand, J.; Guerrero, J. A.; Katana, A. A.; Kato, D.; Lazerwith, S. E.; Li, J.; Link, J. O.; Mai, N., (Gilead Sciences, Inc.). Azabicyclyloxyalkylpyrrolidinone Derivatives as Syk Inhibitors and Their Preparation. International Patent WO 2015017610 A1, 2015.
  There is no corresponding record for this reference.
438. 438
  Mendez-Perez, M.; Breitschopf, K.; Lorenz, K.; Strobel, H.; Wang, L.-H.; Schiffer, A.; Goerlitzer, J. (Sanofi). Preparation of Thienomethylpiperazine Derivatives as Inhibitors of Soluble Epoxide Hydrolase for Therapy. International Patent WO 2015082474 A1, 2015.
  There is no corresponding record for this reference.
439. 439
  Santella, J. B.; Kumar, S. R.; Duncia, J. V.; Gardner, D. S.; Paidi, V. R.; Nair, S. K.; Hynes, J.; Wu, H.; Murugesan, N.; Sarkunam, K.; Arunachalam, P. (Bristol-Myers Squibb Co.). Heteroaryl-Substituted Nicotinamide Compounds as IRAK4 Inhibitors and Their Preparation. International Patent WO 2015103453 A1, 2015.
  There is no corresponding record for this reference.
440. 440
  Sharma, R.; Halder, S.; Kumar, S.; Mascarenhas, M. (Piramal Enterprises Ltd.). Substituted Oxetane Derivatives as GPR40 Agonists and Their Preparation and Use for the Treatment Of GPR40-Mediated Diseases. International Patent WO 2015028960 A1, 2015.
  There is no corresponding record for this reference.
441. 441
  Vrudhula, V. M.; Pan, S.; Rajamani, R.; Macor, J. E.; Bronson, J. J.; Dzierba, C. D.; Nara, S. J.; Karatholuvhu, M. S. (Bristol-Myers Squibb Co.). Preparation of Chromenopyridine Derivatives for Use as Adaptor Associated Kinase 1 Inhibitors. International Patent WO 2015038112 A1, 2015.
  There is no corresponding record for this reference.
442. 442
  Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. 2-Lithiated-2-phenyloxetane: A New Attractive Synthon for the Preparation of Oxetane Derivatives Chem. Commun. 2011, 47, 9918– 9920 DOI: 10.1039/c1cc13670d
  There is no corresponding record for this reference.
443. 443
  Geden, J. V.; Beasley, B. O.; Clarkson, G. J.; Shipman, M. Asymmetric Synthesis of 2-Substituted Oxetan-3-ones via Metalated SAMP/RAMP Hydrazones J. Org. Chem. 2013, 78, 12243– 12250 DOI: 10.1021/jo4020485
  443
  Asymmetric Synthesis of 2 Substituted Oxetan-3-ones via Metalated SAMP/RAMP Hydrazones
  Geden, Joanna V.; Beasley, Benjamin O.; Clarkson, Guy J.; Shipman, Michael
  Journal of Organic Chemistry (2013), 78 (23), 12243-12250CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  2-Substituted oxetan-3-ones can be prepd. in good yields and enantioselectivities (up to 84% ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Addnl., both chiral 2,2- and 2,4-disubstituted oxetan-3-ones can be made in high ee (86-90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aq. oxalic acid provides the 2-substituted oxetan-3-ones without detectable racemization.
444. 444
  Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. The SAMP-/RAMP-Hydrazone Methodology in Asymmetric Synthesis Tetrahedron 2002, 58, 2253– 2329 DOI: 10.1016/S0040-4020(02)00080-7
  444
  The SAMP/RAMP-hydrazone methodology in asymmetric synthesis
  Job, Andreas; Janeck, Carsten F.; Bettray, Wolfgang; Peters, Rene; Enders, Dieter
  Tetrahedron (2002), 58 (12), 2253-2329CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
  A review. Stereoselective reactions of SAMP hydrazones, i,.e., N-alkylidene-(2S)-2-(methoxymethyl)-1-pyrrolidinamine derivs., and of RAMP hydrazones, i.e., N-alkylidene-(2R)-2-(methoxymethyl)-1-pyrrolidinamine derivs., were discussed.
445. 445
  Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Exploiting the Lithiation-Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2-Aryloxetane Scaffolds under Mild Conditions Angew. Chem., Int. Ed. 2012, 51, 7532– 7536 DOI: 10.1002/anie.201109113
  There is no corresponding record for this reference.
446. 446
  Rouquet, G.; Blakemore, D. C.; Ley, S. V. Highly Regioselective Lithiation of Pyridines Bearing an Oxetane Unit by n-Butyllithium Chem. Commun. 2014, 50, 8908– 8911 DOI: 10.1039/C4CC03766A
  There is no corresponding record for this reference.
447. 447
  Ravelli, D.; Zoccolillo, M.; Mella, M.; Fagnoni, M. Photocatalytic Synthesis of Oxetane Derivatives by Selective C-H Activation Adv. Synth. Catal. 2014, 356, 2781– 2786 DOI: 10.1002/adsc.201400027
  447
  Photocatalytic synthesis of oxetane derivatives by selective C-H activation
  Ravelli, Davide; Zoccolillo, Matteo; Mella, Mariella; Fagnoni, Maurizio
  Advanced Synthesis & Catalysis (2014), 356 (13), 2781-2786CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The selective C(sp3)-H activation at position 2 in oxetanes was accomplished by decatungstate photocatalysis under mild conditions. The resulting α-oxy radicals were trapped by electron-poor olefins resulting in the smooth prepn. of 2-substituted oxetanes. The chemoselectivity in hydrogen abstraction in substituted oxetanes contg. other H donating groups, such as CH2OH, CH2OAc and CHO, was demonstrated in intramol. models.
448. 448
  Jin, J.; MacMillan, D. W. C. Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C-H Functionalization and the Minisci Reaction Angew. Chem., Int. Ed. 2015, 54, 1565– 1569 DOI: 10.1002/anie.201410432
  448
  Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C-H Functionalization and the Minisci Reaction
  Jin, Jian; MacMillan, David W. C.
  Angewandte Chemie, International Edition (2015), 54 (5), 1565-1569CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The direct α-arylation of cyclic and acyclic ethers with heteroarenes was accomplished through the design of a photoredox-mediated C-H functionalization pathway. Transiently generated α-oxyalkyl radicals, produced from a variety of widely available ethers through hydrogen atom transfer, were coupled with a range of electron-deficient heteroarenes in a Minisci-type mechanism. This mild, visible-light-driven protocol allowed direct access to medicinal pharmacophores of broad utility using feedstock substrates and a com. photocatalyst.
449. 449
  Ahlgren, G. Reactions of Lone Pair Electron Donors with Unsaturated Electrophiles. I. The Addition of Tetrahydrofuran and Oxetane to Dimethyl Acetylenedicarboxylate J. Org. Chem. 1973, 38, 1369– 1374 DOI: 10.1021/jo00947a028
  There is no corresponding record for this reference.
450. 450
  Arnold, D. R.; Glick, A. H. The Photocycloaddition of Carbonyl Compounds to Allenes Chem. Commun. 1966, 813– 814 DOI: 10.1039/c19660000813
  There is no corresponding record for this reference.
451. 451
  Gotthardt, H.; Steinmetz, R.; Hammond, G. S. Photocyclic Addition of Carbonyl Compounds to Allenes Chem. Commun. 1967, 480– 482 DOI: 10.1039/c19670000480
  There is no corresponding record for this reference.
452. 452
  Gotthardt, H.; Steinmetz, R.; Hammond, G. S. Mechanisms of Photochemical Reactions in Solution. Cycloaddition of Carbonyl Compounds to Allenes J. Org. Chem. 1968, 33, 2774– 2780 DOI: 10.1021/jo01271a035
  There is no corresponding record for this reference.
453. 453
  Hudrlik, P. F.; Hudrlik, A. M. α-Methyleneoxetane Tetrahedron Lett. 1971, 12, 1361– 1364 DOI: 10.1016/S0040-4039(01)96710-3
  There is no corresponding record for this reference.
454. 454
  Hudrlik, P. F.; Hudrlik, A. M.; Wan, C.-N. α-Methyleneoxetane. Study of a Retro-Diels-Alder Reaction J. Org. Chem. 1975, 40, 1116– 1120 DOI: 10.1021/jo00896a027
  There is no corresponding record for this reference.
455. 455
  Hudrlik, P. F.; Mohtady, M. M. Preparation of a Substituted α-Methyleneoxetane by an Intramolecular Alkylation Reaction J. Org. Chem. 1975, 40, 2692– 2963 DOI: 10.1021/jo00906a031
  There is no corresponding record for this reference.
456. 456
  Dollinger, L. M.; Howell, A. R. A Versatile Preparation of 2-Methyleneoxetanes J. Org. Chem. 1996, 61, 7248– 7249 DOI: 10.1021/jo9611733
  456
  A versatile preparation of 2-methyleneoxetanes
  Dollinger, Lisa M.; Howell, Amy R.
  Journal of Organic Chemistry (1996), 61 (21), 7248-7249CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The prepn. of 2-methyleneoxetanes by a novel application of Petasis methylenation to β-lactones is delineated. The methylenation of the β-lactone occurs preferentially in the presence of alkenes and ketones.
457. 457
  Dollinger, L. M.; Howell, A. R. A 2-Methyleneoxetane Analogue of Orlistat Demonstrating Inhibition of Porcine Pancreatic Lipase Bioorg. Med. Chem. Lett. 1998, 8, 977– 978 DOI: 10.1016/S0960-894X(98)00140-1
  There is no corresponding record for this reference.
458. 458
  Zhi, J.; Melia, A. T.; Guerciolini, R.; Chung, J.; Kinberg, J.; Hauptman, J. B.; Patel, I. H. Retrospective Population-Based Analysis of the Dose-Response (Fecal Fat Excretion) Relationship of Orlistat in Normal and Obese Volunteers Clin. Pharmacol. Ther. 1994, 56, 82– 85 DOI: 10.1038/clpt.1994.104
  458
  Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers
  Zhi J; Melia A T; Guerciolini R; Chung J; Kinberg J; Hauptman J B; Patel I H
  Clinical pharmacology and therapeutics (1994), 56 (1), 82-5 ISSN:0009-9236.
  Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.
459. 459
  Borgström, B. Mode of Action of Tetrahydrolipstatin: A Derivative of the Naturally Occurring Lipase Inhibitor Lipstatin Biochim. Biophys. Acta, Lipids Lipid Metab. 1988, 962, 308– 316 DOI: 10.1016/0005-2760(88)90260-3
  There is no corresponding record for this reference.
460. 460
  Cudrey, C.; van Tilbeurgh, H.; Gargouri, Y.; Verger, R. Inactivation of Pancreatic Lipases by Amphilphilic Reagents 5-(Dodecyldithio)-2-Nitrobenzoic Acid and Tetrahydrolipstatin. Dependence Upon Partitioning Between Micellar and Oil Phases Biochemistry 1993, 32, 13800– 13808 DOI: 10.1021/bi00213a008
  There is no corresponding record for this reference.
461. 461
  Fang, Y.; Li, C. Preference of 4-exo Ring Closure in Copper-Catalyzed Intramolecular Coupling of Vinyl Bromides with Alcohols J. Am. Chem. Soc. 2007, 129, 8092– 8093 DOI: 10.1021/ja072793w
  461
  Preference of 4-exo Ring Closure in Copper-Catalyzed Intramolecular Coupling of Vinyl Bromides with Alcohols
  Fang, Yewen; Li, Chaozhong
  Journal of the American Chemical Society (2007), 129 (26), 8092-8093CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The copper-catalyzed intramol. O-vinylation of γ-bromohomoallylic alcs. was investigated. With 10 mol % of CuI as the catalyst and 20 mol % of 1,10-phenanthroline as the ligand, the reactions of 3-bromo-3-buten-1-ols, e.g. I, in refluxing CH3CN led to the convenient formation of the corresponding 2-methyleneoxetanes, e.g. II, in good to excellent yields via a 4-exo ring closure. The configuration of the C:C bond was nicely retained. This methodol. was then successfully extended to the cyclization in 5-exo, 6-exo, and even 6-endo modes. The competition expts. revealed that 4-exo cyclization is fundamentally preferred over other modes of cyclization, while the corresponding Pd(0)-catalyzed O-vinylation showed the predominance of 5-exo over 4-exo cyclization.
462. 462
  Saunders, L. B.; Miller, S. J. Divergent Reactivity in Amine- and Phosphine-Catalyzed C–C Bond-Forming Reactions of Allenoates with 2,2,2-Trifluoroacetophenones ACS Catal. 2011, 1, 1347– 1350 DOI: 10.1021/cs200406d
  462
  Divergent Reactivity in Amine- and Phosphine-Catalyzed C-C Bond-Forming Reactions of Allenoates with 2,2,2-Trifluoroacetophenones
  Saunders, Lindsey B.; Miller, Scott J.
  ACS Catalysis (2011), 1 (10), 1347-1350CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  A divergent reactivity pattern of allenoates with 2,2,2-trifluoroacetophenones under Lewis base catalysis is reported. Whereas phosphine catalysis leads to a [3 + 2]-cycloaddn. to form dihydrofurans, an alternative pathway was discovered in which 1,4-diazabicyclo[2.2.2]octane catalyzes a formal [2 + 2]-cycloaddn. to form oxetanes. This unusual mode of reactivity leads to structurally complex products in moderate to excellent yields (32-86%) and adds to the repertoire of Lewis base-catalyzed allenoate transformations.
463. 463
  Wang, T.; Chen, X.-Y.; Ye, S. DABCO-Catalyzed [2+2] Cycloaddition Reactions of Allenoates and Trifluoromethylketones: Synthesis of 2-Alkyleneoxetanes Tetrahedron Lett. 2011, 52, 5488– 5490 DOI: 10.1016/j.tetlet.2011.08.057
  There is no corresponding record for this reference.
464. 464
  Zhao, Q.-Y.; Huang, L.; Wei, Y.; Shi, M. Catalytic Asymmetric Synthesis of 2-Alkyleneoxetanes Through [2+2] Annulation of Allenoates with Trifluoromethyl Ketones Adv. Synth. Catal. 2012, 354, 1926– 1932 DOI: 10.1002/adsc.201200237
  464
  Catalytic Asymmetric Synthesis of 2-Alkyleneoxetanes through [2+2] Annulation of Allenoates with Trifluoromethyl Ketones
  Zhao, Qian-Yi; Huang, Long; Wei, Yin; Shi, Min
  Advanced Synthesis & Catalysis (2012), 354 (10), 1926-1932, S1926/1-S1926/72CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first example of a β-isocupreidine-catalyzed highly enantioselective [2+2] annulation of allenoates with trifluoromethyl ketones has been disclosed, allowing the synthesis of optically active 2-alkyleneoxetanes in moderate to good yields with good to high enantioselectivities and high diastereoselectivities. E.g., in presence of β-isocupreidine, enantioselective [2+2] annulation of benzyl 2,3-butadienoate and PhCOCF3 gave 74% oxetane (S)-(E)-I. Further transformations of the cycloadducts have been disclosed to afford biol. interesting 6-trifluoromethyl-5,6-dihydropyran-2-ones and trifluoromethyl β-keto acids in good yields.
465. 465
  Selig, P.; Turočkin, A.; Raven, W. Synthesis of Highly Substituted Oxetanes via [2+2] Cycloaddition Reactions of Allenoates Catalyzed by a Guanidine Lewis Base Chem. Commun. 2013, 49, 2930– 2932 DOI: 10.1039/c3cc40855h
  465
  Synthesis of highly substituted oxetanes via [2+2] cycloaddition reactions of allenoates catalyzed by a guanidine Lewis base
  Selig, Philipp; Turockin, Aleksej; Raven, William
  Chemical Communications (Cambridge, United Kingdom) (2013), 49 (28), 2930-2932CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  The first synthesis of highly substituted 3-alkyl-oxetan-2-ylidenes from allenoates was developed by using the bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as an exceptionally active nitrogen Lewis base catalyst.
466. 466
  Selig, P.; Turočkin, A.; Raven, W. Guanidine-Catalyzed Triple Functionalization of γ-Substituted Allenoates with Aldehydes by a Four-Step Reaction Cascade Adv. Synth. Catal. 2013, 355, 297– 302 DOI: 10.1002/adsc.201200807
  466
  Guanidine-catalyzed triple functionalization of γ-substituted allenoates with aldehydes by a four-step reaction cascade
  Selig, Philipp; Turockin, Aleksej; Raven, William
  Advanced Synthesis & Catalysis (2013), 355 (2-3), 297-302CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was discovered as an efficient catalyst for the reaction of γ-substituted allenoates with arom. aldehydes. 4H-1,3-Dioxin-6-ylpropanoates with four newly formed bonds and four stereogenic centers were obtained in good yields and excellent diastereoselectivities by two consecutive Morita-Baylis-Hillman reactions, acetalization and intramol. Michael addn. This four-step reaction cascade not only significantly expands the scope of catalytic allenoate functionalizations but also highlights the potential of TBD to act as a multifunctional Lewis base catalyst.
467. 467
  Dollinger, L. M.; Howell, A. R. An Unanticipated Ring Opening of 2-Methyleneoxetanes: A Fundamentally New Approach to the Preparation of Homopropargylic Alcohols J. Org. Chem. 1998, 63, 6782– 6783 DOI: 10.1021/jo9816360
  There is no corresponding record for this reference.
468. 468
  Wang, Y.; Bekolo, H.; Howell, A. R. Ring Opening Reactions of 2-Methyleneoxetanes Tetrahedron 2002, 58, 7101– 7107 DOI: 10.1016/S0040-4020(02)00724-X
  468
  Ring opening reactions of 2-methyleneoxetanes
  Wang, Ying; Bekolo, Henri; Howell, Amy R.
  Tetrahedron (2002), 58 (35), 7101-7107CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
  Ring opening of 2-methyleneoxetanes with stabilized carbanion nucleophiles provides substituted ketones. The intermediate enolate can be trapped as its silylenol ether. If the 2-methyleneoxetane is exposed to more strongly basic carbanions, the corresponding homopropargylic alc. is isolated in excellent yield. A variety of heteroatom nucleophiles also open the 2-methyleneoxetane in good to excellent yields.
469. 469
  Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang, G.; Wang, Y.; Martinez, I.; Arcari, J. T.; Galluzzo, D. J.; Howell, A. R.; Rheingold, A. L.; Figuero, J. S. Preparation and Properties of 2-Methyleneoxetanes J. Org. Chem. 1999, 64, 7074– 7080 DOI: 10.1021/jo9906072
  469
  Preparation and properties of 2-methyleneoxetanes
  Dollinger, Lisa M.; Ndakala, Albert J.; Hashemzadeh, Mehrnoosh; Wang, Gan; Wang, Ying; Martinez, Isamir; Arcari, Joel T.; Galluzzo, David J.; Howell, Amy R.; Rheingold, Arnold L.; Figuero, Joshua S.
  Journal of Organic Chemistry (1999), 64 (19), 7074-7080CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The methylenation of β-lactones I [R, R1 = H, Me, Ph, allyl, 5-hexenoyl, Bz, PhC(O-TBDMS)H, TBDPS-OCH2CH2, 3-butenyl, Boc-NH, etc. (TBDMS = Me3CSiMe2; TBDPS = Me3CSiPh2; Boc = Me3CO2C)] with dimethyltitanocene provides a versatile, reliable, and highly chemoselective entry to 2-methyleneoxetanes II. The conversion proceeds selectively in the presence of alkenes, unprotected alcs., and a variety of other carbonyl moieties. A study of conditions for the optimization of this reaction is delineated. In addn., the first x-ray crystal structure of a 2-methyleneoxetane S-II (R = BocNH, R1 = R2 = H), which shows its similarity to related β-lactones, is reported. Reactivity studies of 2-methyleneoxetanes are presented in which it is demonstrated that these compds. are attacked at C-4 with a nucleophile and then, subsequently, the resultant enolate reacted with an electrophile. An interesting dichotomy of reactivity was obsd. when methyleneoxetane II (R = Ph; R1 = Me; R2 = H) (III) was treated with electrophiles. Reaction of III with acetic acid gave acetoxyoxetane IV. When III was exposed to bromine, dibromo ketone BrCH2C(Ph)MeCOCH2Br resulted.
470. 470
  Hashemzadeh, M.; Howell, A. R. Reductive Cleavage of 2-Methyleneoxetanes with Lithium and 4, 4′-Di-tert-butylbiphenyl Tetrahedron Lett. 2000, 41, 1855– 1858 DOI: 10.1016/S0040-4039(00)00059-9
  There is no corresponding record for this reference.
471. 471
  Hashemzadeh, M.; Howell, A. R. An Unusual and Efficient Reaction of 2-Methylene-3-Phenyloxetane in the Presence of Lithium and 4,4′-Di-Tert-Butylbiphenyl in THF Tetrahedron Lett. 2000, 41, 1859– 1862 DOI: 10.1016/S0040-4039(00)00060-5
  There is no corresponding record for this reference.
472. 472
  Farber, E.; Rudnitskaya, A.; Keshipeddy, S.; Lao, K. S.; Gascón, J. A.; Howell, A. R. Silicon Acceleration of a Tandem Alkene Isomerization/Electrocyclic Ring-opening of 2-Methyleneoxetanes to α,β-Unsaturated Methylketones J. Org. Chem. 2013, 78, 11213– 11220 DOI: 10.1021/jo4014645
  472
  Silicon Acceleration of a Tandem Alkene Isomerization/Electrocyclic Ring-opening of 2-Methyleneoxetanes to α,β-Unsaturated Methylketones
  Farber, Elisa; Rudnitskaya, Aleksandra; Keshipeddy, Santosh; Lao, Kendricks S.; Gascon, Jose A.; Howell, Amy R.
  Journal of Organic Chemistry (2013), 78 (22), 11213-11220CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The first rearrangement of 2-methyleneoxetanes to α,β-unsatd. methylketones is reported. It is proposed that when these substrates are heated, the corresponding oxetenes are formed and subsequently undergo electrocyclic ring-opening to Me vinyl ketones. In particular, α-silyl-α,β-unsatd. Me ketones were isolated in moderate to high yields and with high stereoselectivities. Based on the proposed mechanism, d. functional theory explains the differential kinetics and stereoselectivities among substrates.
473. 473
  Ferrer, M.; Gibert, M.; Sánchez-Baeza, F.; Messeguer, A. Easy Availability of More Concentrated and Versatile Dimethyldioxirane Solutions Tetrahedron Lett. 1996, 37, 3585– 3586 DOI: 10.1016/0040-4039(96)00628-4
  473
  Easy availability of more concentrated and versatile dimethyldioxirane solutions
  Ferrer, Marta; Gilbert, Mariona; Sanchez-Baeza, Francisco; Messeguer, Angel
  Tetrahedron Letters (1996), 37 (20), 3585-3586CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
  Useful and more concd. solns. of dimethyldioxirane were obtained by extn. with CH2Cl2, CHCl3, or CCl4 and subsequent washing with a phosphate buffer soln.
474. 474
  Howell, A. R.; Ndakala, A. J. Ring Opening of Ketones or 2,2-Disubstituted Oxetanes Org. Lett. 1999, 1, 825– 827 DOI: 10.1021/ol990039c
  There is no corresponding record for this reference.
475. 475
  Taboada, R.; Ordonio, G. G.; Ndakala, A. J.; Howell, A. R.; Rablen, P. R. Directed Ring-Opening of 1,5-Dioxaspiro[3.2]hexanes: Selective Formation of 2,2-Disubstituted Oxetanes J. Org. Chem. 2003, 68, 1480– 1488 DOI: 10.1021/jo0206465
  475
  Directed Ring-Opening of 1,5-Dioxaspiro[3.2]hexanes: Selective Formation of 2,2-Disubstituted Oxetanes
  Taboada, Rosa; Ordonio, Grace G.; Ndakala, Albert J.; Howell, Amy R.; Rablen, Paul R.
  Journal of Organic Chemistry (2003), 68 (4), 1480-1488CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  1,5-Dioxaspiro[3.2]hexanes undergo ring-opening reactions with many heteroatom nucleophiles to provide α-substituted-β'-hydroxy ketones. However, certain Lewis acidic nucleophiles provide 2,2-disubstituted oxetanes. Herein, the results of reactions of 3-phenyl-1,5-dioxaspiro[3.2]hexane with a variety of N-contg. heteroarom. bases are reported. There appears to be a correlation between the pKa of the nucleophile and the reaction outcome with more acidic nucleophiles providing 2,2-disubstituted oxetanes. also, the mode of ring opening can be directed toward the substituted oxetane by the addn. of a Lewis acid. These results are rationalized by calcn. of stationary points on the potential energy surfaces for the various possible reaction pathways using ab initio MO methods.
476. 476
  Ndakala, A. J.; Hashemzadeh, M.; So, R. C.; Howell, A. R. Synthesis of D-erythro-Dihydrosphingosine and D-xylo-Phytosphingosine from a Serine-Derived 1,5-Dioxaspiro[3.2]hexane Template Org. Lett. 2002, 4, 1719– 1722 DOI: 10.1021/ol0200448
  There is no corresponding record for this reference.
477. 477
  Blauvelt, M. L.; Howell, A. R. Synthesis of epi-Oxetin via a Serine-Derived 2-Methyleneoxetane J. Org. Chem. 2008, 73, 517– 521 DOI: 10.1021/jo7018762
  There is no corresponding record for this reference.
478. 478
  Keshipeddy, S.; Martínez, I.; Castillo, B. F.; Morton, M. D.; Howell, A. R. Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles J. Org. Chem. 2012, 77, 7883– 7890 DOI: 10.1021/jo301048z
  478
  Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles
  Keshipeddy, Santosh; Martinez, Isamir; Castillo, Bernard F.; Morton, Martha D.; Howell, Amy R.
  Journal of Organic Chemistry (2012), 77 (18), 7883-7890CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  (compd. nos. in this abstr. correspond to their resp. Roman numerals in the graphic.). Laureatin (1), a metabolite of the red algae Laurencia nipponica, has shown potent activity as a mosquito larvicide. The two previously published syntheses of laureatin involved an initial prepn. of the 8-membered cyclic ether, followed by formation of the oxetane ring. Our strategy was the reverse, i.e., to utilize an oxetane as the framework to construct the larger ring. During this work, attempted N-bromosuccinimide (NBS)-mediated cyclization of oxetane alc. 17, prepd. from readily accessible 2-methyleneoxetane 12, yielded epoxytetrahydrofuran 19 rather than the expected laureatin core. Further derivatization of 19 yielded trans fused bis-tetrahydrofuran 32. The synthesis of 19 and 32, as well as structural and stereochem. elucidation studies, are described.
479. 479
  Wang, G.; Wang, Y.; Arcari, J. T.; Howell, A. R.; Rheingold, A. L.; Concolino, T. 1-Iodomethyl-3,4-diphenyl-2,6-dioxabicyclo[2.2.0]hexane: The First Example of a Fused Ketal Tetrahedron Lett. 1999, 40, 7051– 7053 DOI: 10.1016/S0040-4039(99)01469-0
  There is no corresponding record for this reference.
480. 480
  Liang, Y.; Hnatiuk, N.; Rowley, J. M.; Whiting, B. T.; Coates, G. W.; Rablen, P. R.; Morton, M.; Howell, A. R. Access to Oxetane-Containing psico-Nucleosides from 2-Methyleneoxetanes: A Role for Neighboring Group Participation? J. Org. Chem. 2011, 76, 9962– 9974 DOI: 10.1021/jo201565h
  480
  Access to Oxetane-Containing psico-Nucleosides from 2-Methyleneoxetanes: A Role for Neighboring Group Participation?
  Liang, Yanke; Hnatiuk, Nathan; Rowley, John M.; Whiting, Bryan T.; Coates, Geoffrey W.; Rablen, Paul R.; Morton, Martha; Howell, Amy R.
  Journal of Organic Chemistry (2011), 76 (24), 9962-9974CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The first psico-oxetanocin analog of the powerful antiviral natural product, oxetanocin A, has been readily synthesized from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were derived from β-lactones prepd. by the carbonylation of epoxides. F+-mediated nucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. Surprisingly, attempted exploitation of anchimeric assistance to increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepd. to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable.
481. 481
  Bekolo, H.; Howell, A. R. Preparation and Reactions of 4-Oxaspiro[2.3]hexanes New J. Chem. 2001, 25, 673– 675 DOI: 10.1039/b010095l
  481
  Preparation and reactions of 4-oxaspiro[2.3]hexanes
  Bekolo, Henri; Howell, Amy R.
  New Journal of Chemistry (2001), 25 (5), 673-675CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  2-Methyleneoxetanes were converted in excellent yields to 4-oxaspiro[2.3]hexanes under modified Simmons-Smith conditions. Treatment of the oxaspirohexanes with BF3·Et2O provided cyclopentanones, cyclobutanones or 4-methylenetetrahydrofurans, depending on the substituents.
482. 482
  Furukawa, J.; Kawabata, N.; Nishimura, J. Synthesis of Cyclopropanes by the Reaction of Olefins with Dialkylzinc and Methylene Iodide Tetrahedron 1968, 24, 53– 58 DOI: 10.1016/0040-4020(68)89007-6
  482
  Synthesis of cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide
  Furukawa, Junji; Kawabata, Nariyoshi; Nishimura, Jun
  Tetrahedron (1968), 24 (1), 53-8CODEN: TETRAB; ISSN:0040-4020.
  A novel synthetic route to cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide is described. The essential feature of the reaction is similar to that of the Simmons-Smith reaction (CA 60: 13109e) which involves the treatment of olefins with methylene iodide and Zn-Cu couple. However, the novel route gives cyclopropanes more easily and is esp. suitable for the conversion of cationically polymerizable olefins such as vinyl ethers into the corresponding cyclopropanes. Olefins of this class, when the Simmons-Smith reaction is employed, sometimes give lower yields of cyclopropanes due to polymn.
483. 483
  Malapit, C. A.; Chitale, S. M.; Thakur, M. S.; Taboada, R.; Howell, A. R. Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans: Scope and Mechanism J. Org. Chem. 2015, 80, 5196– 5209 DOI: 10.1021/acs.joc.5b00604
  483
  Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans: Scope and Mechanism
  Malapit, Christian A.; Chitale, Sampada M.; Thakur, Meena S.; Taboada, Rosa; Howell, Amy R.
  Journal of Organic Chemistry (2015), 80 (10), 5196-5209CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A novel Pt-catalyzed rearrangement of oxaspirohexanes, e.g. I, to 3-methylenetetrahydrofurans, e.g. II, is reported. Mechanistic studies by 13C-labeling expts. confirm oxidative addn. of Pt(II) regioselectively to the least substituted carbon-carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been obsd. spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described.
484. 484
  Pritchard, J. G.; Long, F. A. The Kinetics of the Hydrolysis of Trimethylene Oxide in Water, Deuterium Oxide and 40% Aqueous Dioxane 1 J. Am. Chem. Soc. 1958, 80, 4162– 4165 DOI: 10.1021/ja01549a012
  There is no corresponding record for this reference.
485. 485
  Xianming, H.; Kellogg, R. M. Acid Catalyzed Ring-Opening Reactions of Optically Pure 2-Aryl-3,3-Dimethyloxetanes Tetrahedron: Asymmetry 1995, 6, 1399– 1408 DOI: 10.1016/0957-4166(95)00173-M
  There is no corresponding record for this reference.
486. 486
  Searles, S.; Gregory, V. P. The Reaction of Trimethylene Oxide with Amines J. Am. Chem. Soc. 1954, 76, 2789– 2790 DOI: 10.1021/ja01639a055
  There is no corresponding record for this reference.
487. 487
  Chini, M.; Crotti, P.; Favero, L.; Macchia, F. Mild LiBF₄-Promoted Aminolysis of Oxetanes Tetrahedron Lett. 1994, 35, 761– 764 DOI: 10.1016/S0040-4039(00)75811-4
  There is no corresponding record for this reference.
488. 488
  Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Aminolysis of Oxetanes: Quite Efficient Catalysis by Lanthanide(III) Trifluoromethansulfonates Tetrahedron Lett. 1994, 35, 7089– 7092 DOI: 10.1016/0040-4039(94)88233-9
  There is no corresponding record for this reference.
489. 489
  Papini, A.; Ricci, A.; Taddei, M.; Seconi, G.; Dembech, P. Regiospecific Conversion of Oxiranes, Oxetanes, and Lactones into Difunctional Nitrogen Compounds via Aminosilanes and Aminostannanes J. Chem. Soc., Perkin Trans. 1 1984, 2261– 2265 DOI: 10.1039/p19840002261
  489
  Regiospecific conversion of oxiranes, oxetanes, and lactones into difunctional nitrogen compounds via aminosilanes and aminostannanes
  Papini, Annamaria; Ricci, Alfredo; Taddei, Maurizio; Seconi, Giancarlo; Dembech, Pasquale
  Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1984), (10), 2261-5CODEN: JCPRB4; ISSN:0300-922X.
  Insertion reactions of Me3SiNEt2 (I) and Me3SnNEt2 (II) into oxirane, oxetane, and lactone rings were examd. The Et2AlCl- or AlCl3-catalyzed reactions of monoalkyloxiranes and monoalkyl- or aryloxetanes gave regioisomerically pure β- and γ-amino alcs., resp.; with polysubstituted oxiranes a low of regioselectivity was generally obsd. Ring-opening reactions of the lactone rings with I gave β-amino acids or ω-hydroxy amides, depending on the ring size. With II, spontaneous ring cleavage of alkyloxiranes and of β-propiolactone occurred with reverse regioselectivity, whereas oxetanes and γ- and δ-lactones were opened with the same regioselectivity as that obtained with I for these systems.
490. 490
  Fernández-Pérez, H.; Etayo, P.; Núñez-Rico, J. L.; Balakrishna, B.; Vidal-Ferran, A. Ring-Opening of Enantiomerically Pure Oxa-Containing Heterocycles with Phosphorus Nucleophiles RSC Adv. 2014, 4, 58440– 58447 DOI: 10.1039/C4RA10432C
  490
  Ring-opening of enantiomerically pure oxa-containing heterocycles with phosphorus nucleophiles
  Fernandez-Perez, Hector; Etayo, Pablo; Nunez-Rico, Jose Luis; Balakrishna, Bugga; Vidal-Ferran, Anton
  RSC Advances (2014), 4 (102), 58440-58447CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A series of oxa-contg. heterocycles (enantiopure epoxide- and oxetane-based substrates) were subjected to ring-opening with phosphorus nucleophiles. The ring-opening reactions proceeded smoothly and the resulting 1,2-, and 1,3-phosphino alcs. were efficiently isolated as stable borane complexes. These derivs. arise from regio- and stereocontrolled synthesis based on ring-opening processes of oxa-contg. heterocycles. The regio- and stereochem. of the resulting chiral products were unequivocally confirmed in many cases via single-crystal x-ray diffraction anal.
491. 491
  Ng, K.; Tran, V.; Minehan, T. A Single-Flask Synthesis of α-Alkylidene and α-Benzylidene Lactones from Ethoxyacetylene, Epoxides/oxetanes, and Carbonyl Compounds Tetrahedron Lett. 2016, 57, 415– 419 DOI: 10.1016/j.tetlet.2015.12.041
  491
  A single-flask synthesis of α-alkylidene and α-benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and carbonyl compounds
  Ng, Kevin; Tran, Vincent; Minehan, Thomas
  Tetrahedron Letters (2016), 57 (3), 415-419CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  Low temp. treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3·OEt2, followed by addn. of aldehydes or ketones and warming to room temp., affords structurally diverse five- and six-membered α-alkylidene and α-benzylidene lactones in good to excellent yields. This one-pot process, in which three new carbon-carbon bonds and a ring are formed, affords substituted α,β-unsatd. lactones of predominantly Z-configuration. The reaction likely occurs via alkyne-carbonyl metathesis of a hydroxy-ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization.
492. 492
  Yamaguchi, M.; Nobayashi, Y.; Hirao, I. The Alkynylation Reaction of Oxetanes Tetrahedron Lett. 1983, 24, 5121– 5122 DOI: 10.1016/S0040-4039(00)94057-7
  There is no corresponding record for this reference.
493. 493
  Yamaguchi, M.; Nobayashi, Y.; Hirao, I. A Ring Opening Reaction of Oxetanes with Lithium Acetylides Promoted by Boron Trifluoride Etherate Tetrahedron 1984, 40, 4261– 4266 DOI: 10.1016/S0040-4020(01)98801-5
  There is no corresponding record for this reference.
494. 494
  Mullis, J. C.; Weber, W. P. Regiospecificity of Reactions of Epoxides and Oxetanes with Trimethylsilyl Cyanide J. Org. Chem. 1982, 47, 2873– 2875 DOI: 10.1021/jo00136a011
  There is no corresponding record for this reference.
495. 495
  Gassman, P. G.; Haberman, L. M. Regiospecfic Opening of Oxetanes with Trimethylsilyl Cyanide – Zinc Iodide. A General Approach to γ-Amino Alcohols Tetrahedron Lett. 1985, 26, 4971– 4974 DOI: 10.1016/S0040-4039(01)80828-5
  There is no corresponding record for this reference.
496. 496
  Carr, S. A.; Weber, W. P. Titanium Tetrachloride Promoted Reactions of Allylic Trimethylsilanes and Oxetane J. Org. Chem. 1985, 50, 2782– 2785 DOI: 10.1021/jo00215a038
  There is no corresponding record for this reference.
497. 497
  Searles, S., Jr.; Pollart, K. A.; Lutz, E. F. Oxetanes. VI. 1 Reductive Cleavage and Substituent Effects J. Am. Chem. Soc. 1957, 79, 948– 951 DOI: 10.1021/ja01561a046
  There is no corresponding record for this reference.
498. 498
  Hudrlik, P. F.; Wan, C.-N. Reactions of Oxetane with Imine Salts Derived from Cyclohexanone J. Org. Chem. 1975, 40, 2963– 2965 DOI: 10.1021/jo00908a027
  There is no corresponding record for this reference.
499. 499
  Yamaguchi, M.; Shibato, K.; Hirao, I. A New Synthesis of δ-Lactones From Oxetanes Tetrahedron Lett. 1984, 25, 1159– 1162 DOI: 10.1016/S0040-4039(01)91549-7
  499
  A new synthesis of δ-lactones from oxetanes
  Yamaguchi, Masahiko; Shibato, Keisuke; Hirao, Ichiro
  Tetrahedron Letters (1984), 25 (11), 1159-62CODEN: TELEAY; ISSN:0040-4039.
  Oxetanes reacted with lithium enolates generated from esters or amides in the presence of F3B.OEt2 to give δ-hydroxy esters or amides in high yield, which were hydrolyzed and converted to δ-lactones. Thus, AcOCMe3 in THF at -78° was treated with (Me2CH)2NLi in THF-hexane for 25 min and then with heptyloxetane I in THF contg. F3B.OEt2 at -95° to -40° for 1.5 h to give 87% undecanoate II. Treatment of II with F3CCO2H in CH2Cl2 gave undecanolide III quant.
500. 500
  Derick, C. G.; Bissell, D. W. Studies of Trimethylene Oxide. I. Preparation and Characterization J. Am. Chem. Soc. 1916, 38, 2478– 2486 DOI: 10.1021/ja02268a023
  There is no corresponding record for this reference.
501. 501
  Searles, S. The Reaction of Trimethylene Oxide with Grignard Reagents and Organolithium Compounds J. Am. Chem. Soc. 1951, 73, 124– 125 DOI: 10.1021/ja01145a045
  501
  The reaction of trimethylene oxide with Grignard reagents and organolithium compounds
  Searles, Scott
  Journal of the American Chemical Society (1951), 73 (), 124-5CODEN: JACSAT; ISSN:0002-7863.
  Dropwise addn. of 60 g. Cl(CH2)3OAc during 45 min. to 65 g. NaOH, 65 g. KOH, and 5 g. H2O at 150-60° and purification (cf. Noller, C.A. 44, 2443i) gave 42-5% (CH2)3O (I). General procedure: addn. of 0.13-0.20 mole I in 3 vols. anhyd. Et2O to 0.18-0.30 mole RMgX (or RLi occasionally) in cold Et2O (formation of a white ppt.), refluxing 1 hr., addn. of 150-200 cc. C6H6, removal of the Et2O by distn., refluxing 4 hrs., cooling, hydrolysis with satd. NH4Cl, extn. with Et2O or CCl4, and distn. of the org. solns. gave the desired R(CH2)3OH (II), characterized generally as the 3,5-dinitrobenzoate or the 1-naphthylurethan. Data (read R and % yield II): Ph, 84% (also 4% Br(CH2)3OH) (III); Ph, 85% from PhLi; 1-C10H7, 80%; 2-C10H7, 60%; 9-fluorenyl, 44% from RLi; PhCH2, 83%; Bu, 28% from BuLi; cyclohexyl, 28% II, also 40% III; Me2CH, 28% II and 12% III; Me3C, 37% Cl(CH2)3OH. Data for new II (read b.p. and nD20): 1-C10H7, b1 118-19°, 1.615 (phenylurethan, m. 75-6°); 2-C10H7, b7 120-1° (phenylurethan, m. 94°); 9-fluorenyl, b0.2 141° (1-naphthylurethan, m. 124-5°). III was prepd. in 54% yield from 0.2 mole I and 0.5 mole anhyd. MgBr2.
502. 502
  Hodgson, D. M.; Norsikian, S. L. M. First Direct Deprotonation–Electrophile Trapping of Simple Epoxides: Synthesis of α,β-Epoxysilanes from Terminal Epoxides Org. Lett. 2001, 3, 461– 463 DOI: 10.1021/ol006948f
  There is no corresponding record for this reference.
503. 503
  Capriati, V.; Florio, S.; Luisi, R. α-Substituted α-Lithiated Oxiranes: Useful Reactive Intermediates Chem. Rev. 2008, 108, 1918– 1942 DOI: 10.1021/cr0683921
  503
  α-Substituted α-Lithiated Oxiranes: Useful Reactive Intermediates
  Capriati, Vito; Florio, Saverio; Luisi, Renzo
  Chemical Reviews (Washington, DC, United States) (2008), 108 (6), 1918-1942CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. This review focuses on generation, reactivity, and synthetic applications of α-metalated oxiranes with special attention addressed to α-lithiated oxiranes.
504. 504
  Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Copper-Catalysed Reactions of Grignard Reagents with Epoxides and Oxetane Tetrahedron Lett. 1979, 20, 1503– 1506 DOI: 10.1016/S0040-4039(01)86190-6
  There is no corresponding record for this reference.
505. 505
  Christensen, S. H.; Holm, T.; Madsen, R. Ring-Opening of Cyclic Ethers with Carbon-Carbon Bond Formation by Grignard Reagents Tetrahedron 2014, 70, 4942– 4946 DOI: 10.1016/j.tet.2014.05.026
  There is no corresponding record for this reference.
506. 506
  Bertolini, F.; Crotti, S.; Di Bussolo, V.; Macchia, F.; Pineschi, M. Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates J. Org. Chem. 2008, 73, 8998– 9007 DOI: 10.1021/jo801568a
  506
  Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates
  Bertolini, Ferruccio; Crotti, Stefano; Di Bussolo, Valeria; Macchia, Franco; Pineschi, Mauro
  Journal of Organic Chemistry (2008), 73 (22), 8998-9007CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings I (X = O, NTs; R = Ph, 3-ClC6H4, 4-MeC6H4) with phenols, including catechol, was achieved by the use of aryl borates (ArO)3B (Ar = Ph, 2-FC6H4, 2-I-4-MeO2CC6H3, etc.) under mild and neutral reaction conditions without the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding β-aryloxy amines II (X = NTs) in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to det. the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization obsd. (up to 93:7 er) was rationalized by an intramol. delivery through a six-membered transition state, giving β-aryloxy alcs. II (X = O) with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcs. obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.
507. 507
  Dai, P.; Dussault, P. H. Intramolecular Reactions of Hydroperoxides and Oxetanes: Stereoselective Synthesis of 1,2-Dioxolanes and 1,2-Dioxanes Org. Lett. 2005, 7, 4333– 4335 DOI: 10.1021/ol051407h
  507
  Intramolecular Reactions of Hydroperoxides and Oxetanes: Stereoselective Synthesis of 1,2-Dioxolanes and 1,2-Dioxanes
  Dai, Peng; Dussault, Patrick H.
  Organic Letters (2005), 7 (20), 4333-4335CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The 5-exo openings of oxetanes by hydroperoxides proceed rapidly and stereospecifically to furnish 1,2-dioxolanes. The corresponding 6-exo cyclizations are slower and proceed with moderate stereoselectivity. In the case of hydroperoxy acetals, 5-exo nucleophilic transfer of alkoxide competes effectively with 6-exo attack by the hydroperoxide.
508. 508
  Han, W. B.; Wu, Y. Facile Perhydrolysis of Oxetanes Catalyzed by Molybdenum Species Org. Lett. 2014, 16, 5706– 5709 DOI: 10.1021/ol502785u
  508
  Facile Perhydrolysis of Oxetanes Catalyzed by Molybdenum Species
  Han, Wei-Bo; Wu, Yikang
  Organic Letters (2014), 16 (21), 5706-5709CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Perhydrolysis of a range of tertiary oxetanes was achieved in synthetically useful yields under mild conditions [e.g., Na2MoO4-gly-catalyzed perhydrolysis of oxetane I with H2O2 in t-BuOMe afforded hydroperoxide II (61%)]. Different functional/protecting groups were tolerated. Similar ring-opening of secondary oxetanes, which had been unfeasible to date, was also realized with ease. With the aid of optically active substrates the perhydrolysis was shown to proceed with significant stereoselectivity.
509. 509
  Sugiyama, Y.-K.; Heigozono, S.; Okamoto, S. Iron-Catalyzed Reductive Magnesiation of Oxetanes to Generate (3-Oxidopropyl)magnesium Reagents Org. Lett. 2014, 16, 6278– 6281 DOI: 10.1021/ol503191w
  509
  Iron-Catalyzed Reductive Magnesiation of Oxetanes to Generate (3-Oxidopropyl)magnesium Reagents
  Sugiyama, Yu-ki; Heigozono, Shiori; Okamoto, Sentaro
  Organic Letters (2014), 16 (24), 6278-6281CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  In the presence of FeCln-(bisphosphine) or FeCln-(2-iminomethylpyridine) (n = 2 or 3), 2-substituted oxetanes reacted with Grignard reagents undergoing reductive magnesiation at the 2-position to afford substituted 3-oxidopropylmagnesium compds., which are useful nucleophiles in reactions with a variety of electrophiles.
510. 510
  Takekoshi, N.; Miyashita, K.; Shoji, N.; Okamoto, S. Generation of a Low-Valent Titanium Species from Titanatrane and its Catalytic Reactions: Radical Ring Opening of Oxetanes Adv. Synth. Catal. 2013, 355, 2151– 2157 DOI: 10.1002/adsc.201300368
  510
  Generation of a Low-Valent Titanium Species from Titanatrane and its Catalytic Reactions: Radical Ring Opening of Oxetanes
  Takekoshi, Naoto; Miyashita, Kenji; Shoji, Noriaki; Okamoto, Sentaro
  Advanced Synthesis & Catalysis (2013), 355 (11-12), 2151-2157CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Treatment of a titanatrane complex with trimethylsilyl chloride and magnesium powder in THF generated a low-valent titanium species. This species catalyzed the radical ring opening of epoxides and oxetanes to produce the corresponding less substituted alcs. The reagent also catalyzed the deallylation and depropargylation of allylic and propargylic ethers, resp., to provide the parent alcs.
511. 511
  Ishida, N.; Nakanishi, Y.; Murakami, M. Reactivity Change of Cyclobutanols towards Isocyanates: Rhodium Favors C-Carbamoylation over O-Carbamoylation Angew. Chem., Int. Ed. 2013, 52, 11875– 11878 DOI: 10.1002/anie.201306343
  511
  Reactivity Change of Cyclobutanols towards Isocyanates: Rhodium Favors C-Carbamoylation over O-Carbamoylation
  Ishida, Naoki; Nakanishi, Yuuta; Murakami, Masahiro
  Angewandte Chemie, International Edition (2013), 52 (45), 11875-11878CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Rhodium catalysts were found to change the reaction path of cyclobutanol derivs. with isocyanates to form a carbon-carbon bond between the reactants. The process involves a ring opening of a cyclobutane deriv. and proceeds to a direct oxygen-addn. of an isocyanate-oxygen-group. The synthesis of the target compds. was achieved by the action of a cyclobutanol deriv. as carbon nucleophile toward an isocyanate group without loss of a carbonyl group. Bis[(1,2,5,6-η)-1,5-cyclooctadiene]di-μ-(hydroxy)dirhodium (rhodium dimer) and 1,1'-bis(diphenylphosphino)ferrocene were used as catalyst system. The title compds. thus formed included a δ-(oxo)alkanamide deriv. (I) and related substances. Cyclobutanol reactants included (1R,6R,7S)-rel-1-methyl-7-phenylbicyclo[4.2.0]octan-7-ol, 2-phenylspiro[3.5]nonan-2-ol, 3-phenyl-3-oxetanol (cyclobutanol analog).
512. 512
  Ng, F. W.; Lin, H.; Danishefsky, S. J. Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine J. Am. Chem. Soc. 2002, 124, 9812– 9824 DOI: 10.1021/ja0204675
  512
  Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine
  Ng, Fay W.; Lin, Hong; Danishefsky, Samuel J.
  Journal of the American Chemical Society (2002), 124 (33), 9812-9824CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The total synthesis of (±)-gelsemine is described. A defining phase of the effort involved recourse to a strategic oxetane ring. It was constructed anticipating an intramol. displacement of the carbon (C17)-oxygen bond. A key intermediate in the stereospecific elaboration of the oxetane linkage was enone I, which was susceptible to two β-face attacks. Three sigmatropic rearrangements were employed in building the bridgehead (C20) and the spiroanilide (C7) quaternary centers en route to gelsemine.
513. 513
  Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J. The Synthesis of a Key Intermediate En Route to Gelsemine: A Program Based on Intramolecular Displacement of the Carbon-Oxygen Bond of a Strategic Oxetane Tetrahedron Lett. 2002, 43, 545– 548 DOI: 10.1016/S0040-4039(01)02212-2
  There is no corresponding record for this reference.
514. 514
  Bach, T.; Kather, K. Intramolecular Nucleophilic Substitution at the C-4 Position of Functionalized Oxetanes: A Ring Expansion for the Construction of Various Heterocycles J. Org. Chem. 1996, 61, 7642– 7643 DOI: 10.1021/jo961436t
  There is no corresponding record for this reference.
515. 515
  Bach, T.; Kather, K.; Krämer, O. Synthesis of Five-, Six-, and Seven-Membered Heterocycles by Intramolecular Ring Opening Reactions of 3-Oxetanol Derivatives J. Org. Chem. 1998, 63, 1910– 1918 DOI: 10.1021/jo971866z
  There is no corresponding record for this reference.
516. 516
  Boxall, R. J.; Grainger, R. S.; Aricò, C. S.; Ferris, L. Intramolecular Ring-Opening Reactions of 1-(2-Methoxyphenyl)-6-oxabicyclo[3.2.0]heptanes: Spirocyclic Dihydrobenzofurans from Fused Bicyclic Oxetanes Synlett 2008, 2008, 25– 28 DOI: 10.1055/s-2007-990921
  There is no corresponding record for this reference.
517. 517
  Zhao, W.; Wang, Z.; Sun, J. Synthesis of Eight-Membered Lactones: Intermolecular [6 + 2] Cyclization of Amphoteric Molecules with Siloxy Alkynes Angew. Chem., Int. Ed. 2012, 51, 6209– 6213 DOI: 10.1002/anie.201200513
  517
  Synthesis of eight-membered lactones: Intermolecular [6+2] cyclization of amphoteric molecules with siloxy alkynes
  Zhao, Wanxiang; Wang, Zhaobin; Sun, Jianwei
  Angewandte Chemie, International Edition (2012), 51 (25), 6209-6213, S6209/1-S6209/114CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  We have designed a new type of (1,6)-amphoteric mol. by appropriate positioning of the oxetane and aldehyde functional groups within a mol. Enabled by this design, we have successfully demonstrated an efficient [6+2] cyclization process between these (1,6)-amphoteric mols. and siloxy alkynes to form a range of eight-membered lactones. Our method represents the first intermol. reaction for the eight-membered lactone synthesis. Preliminary mechanistic anal. suggests that this unusual process involves a sequence of several selective ring-opening/ring-closing events with concomitant bond formation and cleavage. This approach is now added to the limited no. of strategies available for the elaboration of medium-sized lactones.
518. 518
  Yadav, J. S.; Singh, V. K.; Srihari, P. Formation of Substituted Tetrahydropyrans through Oxetane Ring Opening: Application to the Synthesis of C1–C17 Fragment of Salinomycin Org. Lett. 2014, 16, 836– 839 DOI: 10.1021/ol403604u
  518
  Formation of Substituted Tetrahydropyrans through Oxetane Ring Opening: Application to the Synthesis of C1-C17 Fragment of Salinomycin
  Yadav, J. S.; Singh, Vinay K.; Srihari, P.
  Organic Letters (2014), 16 (3), 836-839CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The stereoselective synthesis of C1-C17 fragment I of salinomycin is achieved. The strategy employs a desymmetrization approach and utilizes an intramol. oxetane ring-opening reaction with O-nucleophile to result in the tetrahydropyran skeleton as the key step.
519. 519
  Yadav, J. S.; Gyanchander, E.; Das, S. Application of oxetane ring opening toward stereoselective synthesis of zincophorin fragment Tetrahedron Lett. 2014, 55, 3996– 3998 DOI: 10.1016/j.tetlet.2014.05.020
  There is no corresponding record for this reference.
520. 520
  Chang, S.; Hur, S.; Britton, R. Total Synthesis of Ascospiroketal A Through a Ag(I)-Promoted Cyclization Cascade Angew. Chem., Int. Ed. 2015, 54, 211– 214 DOI: 10.1002/anie.201408905
  There is no corresponding record for this reference.
521. 521
  Chang, S.; Hur, S.; Britton, R. Total Synthesis and Configurational Assignment of Ascospiroketal A Chem. - Eur. J. 2015, 21, 16646– 16653 DOI: 10.1002/chem.201502754
  521
  Total Synthesis and Configurational Assignment of Ascospiroketal A
  Chang, Stanley; Hur, Soo; Britton, Robert
  Chemistry - A European Journal (2015), 21 (46), 16646-16653CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The total synthesis of the marine fungus-derived natural product ascospiroketal is described. This concise synthesis relies on a unique AgI-promoted tandem cascade cyclization that provides direct access to the correctly configured tricyclic core of the natural product from a linear precursor. The synthesis of candidate stereostructures of ascospiroketal A allowed for the confident assignment of both the relative and abs. stereochem. of this unusual octaketide as I.
522. 522
  Mizuno, M.; Kanai, M.; Iida, A.; Tomioka, K. An External Chiral Ligand Controlled Enantioselective Opening of Oxirane and Oxetane by Organolithiums Tetrahedron 1997, 53, 10699– 10708 DOI: 10.1016/S0040-4020(97)00701-1
  522
  An external chiral ligand controlled enantioselective opening of oxirane and oxetane by organolithiums
  Mizuno, Masashi; Kanai, Motomu; Iida, Akira; Tomioka, Kiyoshi
  Tetrahedron (1997), 53 (31), 10699-10708CODEN: TETRAB; ISSN:0040-4020. (Elsevier)
  Enantioselective nucleophilic opening reactions of cyclohexene oxide and 3-phenyloxetane were achieved by the combination of an external chiral ligand and organolithiums in the presence of boron trifluoride to give the corresponding alcs. in up to 47% ee.
523. 523
  Loy, R. N.; Jacobsen, E. N. Enantioselective Intramolecular Openings of Oxetanes Catalyzed by (salen)Co(III) Complexes: Access to Enantioenriched Tetrahydrofurans J. Am. Chem. Soc. 2009, 131, 2786– 2787 DOI: 10.1021/ja809176m
  523
  Enantioselective Intramolecular Openings of Oxetanes Catalyzed by (salen)Co(III) Complexes: Access to Enantioenriched Tetrahydrofurans
  Loy, Rebecca N.; Jacobsen, Eric N.
  Journal of the American Chemical Society (2009), 131 (8), 2786-2787CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The catalytic enantioselective intramol. ring-opening of oxetanes with alcs., e.g. I (R = H, Me, Ph, i-Pr, F, etc.), is catalyzed by (salen)Co(III) complexes. Either a monomeric or oligomeric catalyst can be used successfully in this transformation, providing 3-substituted tetrahydrofurans, e.g. II, in both high yield and enantioselectivity. This methodol. extends the range of electrophiles that can be activated toward highly enantioselective addn. reactions by (salen)metal catalysts to an important new class.
524. 524
  Chen, Z.; Wang, Z.; Sun, J. Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of (+)-(8S,13R)- Cyclocelabenzine Chem. - Eur. J. 2013, 19, 8426– 8430 DOI: 10.1002/chem.201301065
  524
  Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of (+)-(8S,13R)-Cyclocelabenzine
  Chen, Zhilong; Wang, Zhaobin; Sun, Jianwei
  Chemistry - A European Journal (2013), 19 (26), 8426-8430CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The authors have developed a multicomponent method for efficient assembly of tetrahydroisoquinolines, which involves the formation of a C4 stereocenter by means of an enantioselective desymmetrization of oxetanes with amine nucleophiles. These tetrahydroisoquinolines can now be synthesized using a one-step catalytic asym. method that with high efficiency and enantioselectivity. Thus, reacting oxetanylbenzaldehyde I with 3,4,5-trimethoxyaniline in the presence of Hanzstch di-Me ester and phosphoric acid catalyst II gave tetrahydroisoquinoline III in up to 97:3 er. The method was applied to the formal synthesis of alkaloid (+)-(8S,13R)-cyclocelabenzine (IV).
525. 525
  Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels-Alder Reaction of Indoles with Oxetane as Directing Group Angew. Chem., Int. Ed. 2013, 52, 2027– 2031 DOI: 10.1002/anie.201206481
  525
  Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels-Alder Reaction of Indoles with Oxetane as Directing Group
  Chen, Zhilong; Wang, Beilei; Wang, Zhaobin; Zhu, Guangyu; Sun, Jianwei
  Angewandte Chemie, International Edition (2013), 52 (7), 2027-2031CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first catalytic asym. three-component aza-Diels-Alder reaction using indole as the dienophile was developed. In this reaction, oxetane was shown to be a superb directing group that played a crucial role in achieving both high yields and high enantioselectivities. Thus, in the presence of a chiral phosphoric acid catalyst, I [Ar = C6H2(CHMe2)-2,4,6], a range of complex polycyclic alkaloid-type mols. that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties were rapidly assembled from simple achiral starting materials. The process features efficient formation of multiple bonds (two C-C and two C-N bonds) and multiple (four) chiral centers, rapid installation of mol. complexity, excellent chem. efficiency and stereoselectivity, easy product purifn., and proven biol. activity of the products. This new catalytic asym. multicomponent reaction should be attractive for diversity-oriented synthesis and drug discovery. Further investigations on the reaction mechanism and biol. properties of the polycyclic alkaloid-type products are underway.
526. 526
  Yang, W.; Sun, J. Organocatalytic Enantioselective Synthesis of 1,4-Dioxanes and Other Oxa-Heterocycles by Oxetane Desymmetrization Angew. Chem., Int. Ed. 2016, 55, 1868– 1871 DOI: 10.1002/anie.201509888
  526
  Organocatalytic Enantioselective Synthesis of 1,4-Dioxanes and Other Oxa-Heterocycles by Oxetane Desymmetrization
  Yang, Wen; Sun, Jianwei
  Angewandte Chemie, International Edition (2016), 55 (5), 1868-1871CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A new asym. synthesis of chiral 1,4-dioxanes and other oxa-heterocycles has been developed by means of organocatalytic enantioselective desymmetrization of oxetanes. This mild process proceeds with exceedingly high efficiency and enantioselectivity to establish the quaternary stereocenters. This method complements the existing, yet limited, strategies for the synthesis of these oxa-heterocycles. Under optimized conditions the synthesis of the target compds. was achieved using (11aR)-10,11,12,13-tetrahydro-5-(hydroxy)-3.7-bis(1-pyrenyl)diindeno[7,1-de:1',7'-fg][1,3,2]dioxaphosphocin as a catalyst. Starting materials included 2-[(3-oxetanyl)oxy]ethanol derivs.
527. 527
  Yang, W.; Wang, Z.; Sun, J. Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl Angew. Chem., Int. Ed. 2016, 55, 6954– 6958 DOI: 10.1002/anie.201601844
  527
  Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl
  Yang, Wen; Wang, Zhaobin; Sun, Jianwei
  Angewandte Chemie, International Edition (2016), 55 (24), 6954-6958CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  In the presence of a nonracemic spirobiindanephosphoric acid, 3-substituted oxetanes underwent enantioselective ring opening and desymmetrization with chloride generated in situ from trimethoxychlorosilane and water in the presence of 5Å mol. sieves in benzene to yield nonracemic chloropropanols such as (R)-HOCH2CHRCH2Cl [R = Ph, 4-MeC6H4, 2-MeOC6H4, 3-BrC6H4, 3-F3CC6H4, 4-F3CC6H4, 2-naphthyl, 2-benzofuranyl, (E)-PhCH:CH, PhCH2, PhCH2O] as highly functionalized three-carbon building blocks. The excellent enantiocontrol is enabled not only by the use of the new spirobiindanephosphoric acid catalyst, but also by the unusual use of wet mol. sieves for the controlled release of HCl.
528. 528
  Burkhard, J. A.; Tchitchanov, B. H.; Carreira, E. M. Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes Angew. Chem., Int. Ed. 2011, 50, 5379– 5382 DOI: 10.1002/anie.201100260
  528
  Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes
  Burkhard, Johannes A.; Tchitchanov, Boris H.; Carreira, Erick M.
  Angewandte Chemie, International Edition (2011), 50 (23), 5379-5382, S5379/1-S5379/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  3-Substituted isoxazole-4-carbaldehydes (I, R = Bn, CH2C6F5, cyclohexylmethyl, CH2CO2Et, etc.) can be prepd. by the condensation reaction of nitroalkanes RCH2NO2 with 3-oxetanone. In general, tertiary amines (in particular iPr2NEt) were superior to other bases in favoring the formation of isoxazoles. The one-pot operation probably involves Henry addn., elimination/condensation, and rearrangement to the isoxazole.
529. 529
  Ruider, S. A.; Müller, S.; Carreira, E. M. Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles Angew. Chem., Int. Ed. 2013, 52, 11908– 11911 DOI: 10.1002/anie.201306563
  529
  Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles
  Ruider, Stefan A.; Mueller, Steffen; Carreira, Erick M.
  Angewandte Chemie, International Edition (2013), 52 (45), 11908-11911CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Spirocycles I (X = O, S, PhN, TsN; R1 = H, Et, Ph, 4-BrC6H4CH2, etc.; R2 = H, Me, i-Pr, n-Bu, Ph, PhCH2, R3 = H; R2 = R3 = Me, Ph; R2R3 = CH2OCMe2OCH2; R4 = H, PhOCH2, R5 = H; R4 = H2C:CH, R5 = Me; etc.) derived from 3-oxetanone and β-heteroatom-substituted amines underwent a Lewis acid mediated reaction cascade with trimethylsilyl cyanide or di-Et trimethylsilyl phosphite to form satd. nitrogen heterocycles II [Y = CN, (EtO)2P(O)]. The unique reactivity of 3-oxetanone facilitates access to biol. important morpholines, piperazines, and thiomorpholines with an otherwise difficult-to-access substitution pattern from readily available starting materials.
530. 530
  Orr, D.; Tolfrey, A.; Percy, J. M.; Frieman, J.; Harrison, Z. A.; Campbell-Crawford, M.; Patel, V. K. Single-Step Microwave-Mediated Synthesis of Oxazoles and Thiazoles from 3-Oxetanone: A Synthetic and Computational Study Chem. - Eur. J. 2013, 19, 9655– 9662 DOI: 10.1002/chem.201301011
  530
  Single-Step Microwave-Mediated Syntheses of Oxazoles and Thiazoles from 3-Oxetanone: A Synthetic and Computational Study
  Orr, David; Tolfrey, Alexandra; Percy, Jonathan M.; Frieman, Joanna; Harrison, Zoe A.; Campbell-Crawford, Matthew; Patel, Vipulkumar K.
  Chemistry - A European Journal (2013), 19 (29), 9655-9662CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calcns. have shown that the order of events involves chalcogen atom attack at sp3 carbon and alkyl-oxygen cleavage. The crit. role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calcd. barriers were also fully consistent with the obsd. order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of C-O cleavage, moderating the extent of strain relief. On the acid-catalyzed pathway, C-O cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid.
531. 531
  Friedrich, K.; Jansen, U.; Kirmse, W. Oxygen Ylides – I. Reactions Of Carbenes With Oxetane Tetrahedron Lett. 1985, 26, 193– 196 DOI: 10.1016/S0040-4039(00)61877-4
  There is no corresponding record for this reference.
532. 532
  Kirmse, W.; Van Chiem, P.; Schurig, V. Oxygen Ylides – II. Photochemical And Rhodium-Catalyzed Reactions Of Diazomethane With (S)-2-Methyloxetane Tetrahedron Lett. 1985, 26, 197– 200 DOI: 10.1016/S0040-4039(00)61878-6
  There is no corresponding record for this reference.
533. 533
  Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Asymmetric Induction in Carbenoid Reaction by Means of a Dissymmetric Copper Chelate Tetrahedron Lett. 1966, 7, 5239– 5244 DOI: 10.1016/S0040-4039(01)89263-7
  There is no corresponding record for this reference.
534. 534
  Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Homogeneous Catalysis in the Decomposition of Diazo Compounds by Copper Chelates: Asymmetric Carbenoid Reactions Tetrahedron 1968, 24, 3655– 3669 DOI: 10.1016/S0040-4020(01)91998-2
  534
  Homogeneous catalysis in the decomposition of diazo compounds by copper chelates. Asymmetric carbenoid reactions
  Nozaki, Hitosi; Takaya, Hidemasa; Moriuti, S.; Noyori, Ryoji
  Tetrahedron (1968), 24 (9), 3655-69CODEN: TETRAB; ISSN:0040-4020.
  Bis(acetylacetonato)copper(II) catalyzes thermal decompn. of diphenyldiazomethane in benzene to afford tetraphenylethylene and benzophenone azine. The absence of 1,1,2,2-tetraphenylethane among the products is explained by assuming a copper carbenoid in which the carbene moiety is attached to the central copper atom as the fifth ligand. The apparently electrophilic nature of this carbenoid is illustrated by isolating cyclopropylamines upon reaction with enamines. Chem. evidence for the postulated coordination has been obtained by observing several instances of asymmetric synthesis, which proceed under influence of a chiral copper chelate, bis[N-(R)-α-phenethylsalicylaldiminato]copper(II) (R)-I, and its enantiomer. The following products were obtained in partially resolved form from reactions of methyl or ethyl diazoacetate and diazomethane with appropriate optically inactive substrates: ethyl cis- and trans-2-phenylcyclopropanecarboxylate, methyl cis- and trans-3-phenyltetrahydrofuran-2-carboxylate, trans-1-methyl-2-phenylcyclopropane, trans-bicyclo[10.1.0]-cis-4,trans-8-tridecadiene and trans-bicyclo[10.1.0]tridecane. Intramol. cyclization of allyl diazoacetate and of 1-diazo-6-phenyl-trans-5-hexene-2-one occurs smoothly in the presence of the same copper chelate to afford 3-oxabicyclo[3.1.0]hexan-2-one and 6-phenylbicyclo[3.1.0]hexan-2-one both in partially resolved state. The mechanism of these carbonoid reactions is discussed on the basis of further addnl. observations. 42 references.
535. 535
  Ito, K.; Katsuki, T. Asymmetric Carbene C-O Insertion Reaction Using Optically Active Bipyridine-Copper Complex as a Catalyst. Ring Expansion of Oxetanes to Tetrahydrofurans Chem. Lett. 1994, 23, 1857– 1860 DOI: 10.1246/cl.1994.1857
  There is no corresponding record for this reference.
536. 536
  Ito, K.; Yoshitake, M.; Katsuki, T. Enantiospecific Ring Expansion of Oxetanes: Stereoselective Synthesis of Tetrahydrofurans Heterocycles 1996, 42, 305– 317 DOI: 10.3987/COM-95-S35
  536
  Enantiospecific ring expansion of oxetanes: stereoselective synthesis of tetrahydrofurans
  Ito, Katsuji; Yoshitake, Miwa; Katsuki, Tsutomu
  Heterocycles (1996), 42 (1), 305-17CODEN: HTCYAM; ISSN:0385-5414. (Japan Institute of Heterocyclic Chemistry)
  Enantiospecific ring expansion of oxetanes to tetrahydrofurans with diazoacetic acid ester was found to be catalyzed by the copper complex of (7R,7'R)-7,7'-di(1-tert-butyldimethylsiloxy-1-methylethyl)-6,6',7,7'-tetrahydro-5H,5'H-2,2'-bi-1,1'-pyridine (4). For example, the reaction of (R)-2-phenyloxetane of 89% ee and tert-Bu diazoacetate with Cu-4 complex as a catalyst provided tert-Bu (2S,3R)-3-phenyltetrahydrofuran-2-carboxylate of 92% ee as a major product, while that of (S)-2-phenyloxetane of 85% ee provided tert-Bu (2S,3S)-3-phenyltetrahydrofuran-2-carboxylate of 93% ee as a major one.
537. 537
  Ito, K.; Yoshitake, M.; Katsuki, T. Enantioselective Synthesis of trans-Whisky Lactone by Using Newly Developed Asymmetric Ring Expansion Reaction of Oxetane as a Key Step Chem. Lett. 1995, 24, 1027– 1028 DOI: 10.1246/cl.1995.1027
  There is no corresponding record for this reference.
538. 538
  Ito, K.; Fukuda, T.; Katsuki, T. A New Methodology for Efficient Construction of 2,7-Dioxabicyclo[3.3.0]octane Derivatives Synlett 1997, 1997, 387– 389 DOI: 10.1055/s-1997-809
  There is no corresponding record for this reference.
539. 539
  Ito, K.; Fukuda, T.; Katsuki, T. A New Enantiospecific Approach to the Bislactone Structure: Formal Synthesis of (−)-Avenaciolide and (−)-Isoavenaciolide Heterocycles 1997, 46, 401– 411 DOI: 10.3987/COM-97-S34
  There is no corresponding record for this reference.
540. 540
  Rix, D.; Ballesteros-Garrido, R.; Zeghida, W.; Besnard, C.; Lacour, J. Macrocyclization of Oxetane Building Blocks with Diazocarbonyl Derivatives under Rhodium(II) Catalysis Angew. Chem., Int. Ed. 2011, 50, 7308– 7311 DOI: 10.1002/anie.201102152
  There is no corresponding record for this reference.
541. 541
  Larksarp, C.; Alper, H. Synthesis of 1,3-Oxazine Derivative by Palladium-Catalyzed Cycloaddition of Vinyloxetanes with Heterocumulenes. Completely Stereoselective Synthesis of Bicyclic 1,3-Oxazines J. Org. Chem. 1999, 64, 4152– 4158 DOI: 10.1021/jo990430b
  There is no corresponding record for this reference.
542. 542
  Mack, D. J.; Batory, L. A.; Njardarson, J. T. Intermolecular Oxonium Ylide Mediated Synthesis of Medium-Sized Oxacycles Org. Lett. 2012, 14, 378– 381 DOI: 10.1021/ol203129d
  542
  Intermolecular Oxonium Ylide Mediated Synthesis of Medium-Sized Oxacycles
  Mack, Daniel J.; Batory, Lindsay A.; Njardarson, Jon T.
  Organic Letters (2012), 14 (1), 378-381CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Detailed in this account are the efforts toward efficient oxacycle syntheses. Two complementary approaches are discussed, with both employing chemoselective allyl ether activation and rearrangement as the key step. Vinyl-substituted oxiranes and oxetanes provide a single step access to dihydropyrans and tetrahydrooxepines. Oxiranes proved to be poor substrates, while oxetanes were slightly better. An alternative approach using substituted allyl ethers proved successful and addressed the limitations encountered in the ring expansions.
543. 543
  Guo, B.; Schwarzwalder, G.; Njardarson, J. T. Catalytic Ring Expansion of Vinyl Oxetanes: Asymmetric Synthesis of Dihydropyrans Using Chiral Counterion Catalysis Angew. Chem., Int. Ed. 2012, 51, 5675– 5678 DOI: 10.1002/anie.201201367
  543
  Catalytic Ring Expansion of Vinyl Oxetanes: Asymmetric Synthesis of Dihydropyrans Using Chiral Counterion Catalysis
  Guo, Boying; Schwarzwalder, Gregg; Njardarson, Jon T.
  Angewandte Chemie, International Edition (2012), 51 (23), 5675-5678, S5675/1-S5675/105CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A catalytic ring expansion reaction of vinyl oxetanes, e.g., I, is described using Cu(OTf)2 as the catalyst. The reaction occurs under mild conditions with a broad scope of substrates. The yields of the pyran derivs., e.g., II, are uniformly excellent. A sym. version of the reaction has been presented using divinyloxetane III, which gives (R)-pyran IV in up to 90% ee depending on the chiral phosphoric acid deriv.
544. 544
  Mack, D. J.; Njardarson, J. T. Recent Advances in the Metal-Catalyzed Ring Expansions of Three- and Four-Membered Rings ACS Catal. 2013, 3, 272– 286 DOI: 10.1021/cs300771d
  544
  Recent Advances in the Metal-Catalyzed Ring Expansions of Three- and Four-Membered Rings
  Mack, Daniel J.; Njardarson, Jon T.
  ACS Catalysis (2013), 3 (2), 272-286CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  A review. New catalytic ring-expansion reactions of strained ring (hetero- and carbocyclic) substrates reported in the last six years (2006-2012) are presented. As evident from the diversity of new approaches, this is a vibrant area of research. Metals ranging from magnesium to gold have been used as catalysts. Some of these reactions allow access to enantioenriched products by employing catalysts decorated with chiral org. motifs (primarily C-2 sym.).
545. 545
  Njardarson, J. T. Catalytic Ring Expansion Adventures Synlett 2013, 24, 787– 803 DOI: 10.1055/s-0032-1318326
  545
  Catalytic ring expansion adventures
  Njardarson, Jon T.
  Synlett (2013), 24 (7), 787-803CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
  A review. This account summarizes the work done by the Njardarson group on ring expansion reactions of earlier vinyl oxirane compds. to more recent vinyl oxetane compds. The evolution of the program and the incredible success of Cu(hfacac)2 as a catalyst are detailed. Applications of these new ring expansion reactions to natural product, pharmaceutical and commodity chem. targets are discussed as well as reaction mechanism studies and chiral counterion catalysis.
546. 546
  Ilardi, E. A.; Njardarson, J. T. Ring Expansions of Vinyloxiranes, -Thiiranes, and -Aziridines: Synthetic Approaches, Challenges, and Catalytic Success Stories J. Org. Chem. 2013, 78, 9533– 9540 DOI: 10.1021/jo401776s
  546
  Ring Expansions of Vinyloxiranes, -thiiranes, and -aziridines: Synthetic Approaches, Challenges, and Catalytic Success Stories
  Ilardi, Elizabeth A.; Njardarson, Jon T.
  Journal of Organic Chemistry (2013), 78 (19), 9533-9540CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A review. Ring expansion reactions of strained vinylic heterocyclic substrates have attracted the attention of the synthetic community for decades. Strategic manipulations of these org. architectures enable access to many useful synthetic intermediates. This paper highlights various methods for the ring expansion of vinyloxiranes, -thiiranes, and -aziridines described in the literature from 1964 to 2013.
547. 547
  Guo, B.; Njardarson, J. T. Z-Selective Ring Opening of Vinyl Oxetanes with Dialkyl Dithiophosphate Nucleophiles Chem. Commun. 2013, 49, 10802– 10804 DOI: 10.1039/c3cc46660d
  547
  Z-Selective ring opening of vinyl oxetanes with dialkyl dithiophosphate nucleophiles
  Guo, Boying; Njardarson, J. T.
  Chemical Communications (Cambridge, United Kingdom) (2013), 49 (92), 10802-10804CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Dialkyl dithiophosphates selectively ring open vinyl oxetanes in excellent yields under mild reaction conditions to form useful allylic thiophosphate products with high Z-selectivity.
548. 548
  Gronnier, C.; Kramer, S.; Odabachian, Y.; Gagosz, F. Cu(I)-Catalyzed Oxidative Cyclization of Alkynyl Oxiranes and Oxetanes J. Am. Chem. Soc. 2012, 134, 828– 831 DOI: 10.1021/ja209866a
  548
  Cu(I)-Catalyzed Oxidative Cyclization of Alkynyl Oxiranes and Oxetanes
  Gronnier, Colombe; Kramer, Soeren; Odabachian, Yann; Gagosz, Fabien
  Journal of the American Chemical Society (2012), 134 (2), 828-831CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  In the presence of a Cu(I) catalyst and a pyridine oxide, alkynyl oxiranes and oxetanes can be converted into functionalized five- or six-membered α,β-unsatd. lactones or dihydrofuranaldehydes. E.g., in presence of Cu(NCMe)4NTf2 and N-pyridine oxide, oxidative cyclization of alkynyl oxirane (I) gave 53% α,β-unsatd. lactone (II). This new oxidative cyclization is proposed to proceed via an unusual allenyloxypyridinium intermediate.
549. 549
  Thakur, A.; Facer, M. E.; Louie, J. Nickel-Catalyzed Cycloaddition of 1,3-Dienes with 3-Azetidinones and 3-Oxetanones Angew. Chem., Int. Ed. 2013, 52, 12161– 12165 DOI: 10.1002/anie.201306869
  549
  Nickel-catalyzed cycloaddition of 1,3-dienes with 3-azetidinones and 3-oxetanones
  Thakur, Ashish; Facer, Megan E.; Louie, Janis
  Angewandte Chemie, International Edition (2013), 52 (46), 12161-12165CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A Ni/P(p-tol)3-catalyzed intermol. cycloaddn. of 1,3-dienes and 3-azetidi- nones/3-oxetanones has been developed. This synthetic method involves C-C activation of the strained four-membered heterocycle to form monocyclic and bicyclic eight-membered heterocyclic products, e.g., I (R = Me, Bn;X = O or N-Boc), which are difficult to access by conventional methods. Interestingly, the use of a diene conjugated with a benzene ring led to the formation of a piperidinone rather than an eight-membered heterocycle.
550. 550
  Pawar, S. K.; Vasu, D.; Liu, R.-S. Gold- and Silver-Catalyzed [4 + 2] Cycloadditions of Ynamides with Oxetanes and Azetidines Adv. Synth. Catal. 2014, 356, 2411– 2416 DOI: 10.1002/adsc.201400024
  550
  Gold- and silver-catalyzed [4+2] cycloadditions of ynamides with oxetanes and azetidines
  Pawar, Samir Kundlik; Vasu, Dhananjayan; Liu, Rai-Shung
  Advanced Synthesis & Catalysis (2014), 356 (11-12), 2411-2416CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Gold-catalyzed [4+2] cycloaddns. between ynamides and oxetanes was carried out; these reactions involve oxetanes and gold-π-ynamides as nucleophiles and electrophiles, resp. Excellent cycloaddn. regioselectivities are achieved over a reasonable range of ynamide and oxetane substrates. For azetidines, their [4+2] cycloaddns. with ynamides are implemented more efficiently with silver hexafluoroantimonate, which is also compatible with various ynamides and azetidines. These two cycloaddns. provide facile accesses to six-membered heterocycles such as 6-amino-3,4-dihydro-2H-pyrans and 2-amino-1,4,5,6-tetrahydropyridines. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
551. 551
  Yin, Q.; You, S.-L. Asymmetric Chlorination/Ring Expansion for the Synthesis of α-Quaternary Cycloalkanones Org. Lett. 2014, 16, 1810– 1813 DOI: 10.1021/ol5005565
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  Asymmetric Chlorination/Ring Expansion for the Synthesis of α-Quaternary Cycloalkanones
  Yin, Qin; You, Shu-Li
  Organic Letters (2014), 16 (6), 1810-1813CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A highly enantioselective chlorination/ring expansion cascade for the construction of cycloalkanones with an all-carbon quaternary center was realized (up to 97% ee). Oxa-cyclobutanol substrates were employed for the first time in the ring expansion reactions, affording the functionalized dihydrofuranones in excellent enantioselectivity.

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal ChemistryClick to copy article linkArticle link copied!

Chemical Reviews

Abstract

1 Introduction

2 Properties and Natural Occurrence of Oxetanes and Their Influence on Biologically Relevant Physicochemical Properties

2.1 Physical Properties of Oxetanes

Figure 1

2.2 Oxetanes in Natural Products

Figure 2

Figure 3

2.3 Oxetanes as Replacement Groups

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

3 Synthesis of Oxetane Derivatives by Intramolecular Cyclization

3.1 Cyclization through C–O Bond Formation

3.1.1 Intramolecular Etherification

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

Scheme 14

Scheme 15

Scheme 16

Scheme 17

3.1.2 Epoxide Ring Opening/Ring Closing

Scheme 18

Scheme 19

Scheme 20

3.1.3 Synthesis of Oxetanes from Sugar Derivatives

Scheme 21

Scheme 22

Scheme 23

Scheme 24

Scheme 25

Scheme 26

Scheme 27

3.1.3.1 C3 Functionalization and Applications of Oxetanes Derived from Sugars

Scheme 28

Scheme 29

Scheme 30

3.1.3.2 C4 Functionalization and Applications of Oxetanes Derived from Sugars

Scheme 31

Scheme 32

Scheme 33

Scheme 34

Scheme 35

3.1.4 Synthesis of Oxetane-Containing Nucleoside Analogues

Figure 13

Scheme 36

Scheme 37

Scheme 38

Figure 14

Scheme 39

Scheme 40

Scheme 41

Scheme 42

3.1.5 Oxetane Synthesis through Electrophilic Halocyclization of Alcohols

Scheme 43

Scheme 44

Scheme 45

Scheme 46

Scheme 47

Scheme 48

Scheme 49

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry
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