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Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization
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Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization
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  • Abigail H. Horchar
    Abigail H. Horchar
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
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  • Jonathan E. Dean
    Jonathan E. Dean
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
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  • Alexander R. Lake
    Alexander R. Lake
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
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  • Jessica E. Carsley
    Jessica E. Carsley
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
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  • Tiana R. Lillevig
    Tiana R. Lillevig
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
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  • Shubin Liu
    Shubin Liu
    Department of Chemistry, The University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, North Carolina 27514, United States
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    Orcidhttps://orcid.org/0000-0001-9331-0427
  • Kimberly S. Petersen*
    Kimberly S. Petersen
    Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    *Email: [email protected]
    More by Kimberly S. Petersen
    Orcidhttps://orcid.org/0000-0002-5020-3549
Open PDFSupporting Information (2)

The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2024, 89, 17, 12725–12738
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https://doi.org/10.1021/acs.joc.4c01060
Published August 9, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

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The enantioenriched lactams disclosed in this work are synthesized concisely in four steps. In the penultimate reaction, a benzylamine species complexes with a chiral phosphoric acid to produce benzo-fused δ-lactams equipped with an all-carbon quaternary stereocenter. Partial and full reductions were carried out on the ester and amide moieties, and a Suzuki–Miyaura cross-coupling expanded the molecule from the aromatic ring. Finally, our method was successful at a >1 g scale, indicating that the method has important practical use.

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Increasing antimicrobial resistance and emerging diseases calls for the scientific community to uncover unique molecules and scaffolds. In this pursuit is the need for improved methods to assemble these structurally relevant motifs. One mission of synthesis is to construct molecules that emulate the functions of valuable natural products. However, a pressing problem is the ability of chemists to synthesize these complex compounds, for the sake of unlocking certain coveted properties, due to elaborate stereochemistry and functional groups. Consequently, chemists need more tools in their toolbox. This drives the development of methodologies to recreate target moieties such as N- and O-containing heterocycles─along with their specific configuration in space. Concurrently, there is considerable literature acknowledging the importance of lactams and their presence in compounds with biological applications. Moreover, works by Akiyama, List, Chen, Sun, and others detail the significance of CPA-catalyzed desymmetrizations. (1−4) The method herein produces enantioenriched lactams with a chiral center α to the carbonyl through a desymmetrization via a chiral phosphoric acid (CPA) catalyst. The compounds in Figure 1 highlight the importance of the fused lactam motif. (5)

Figure 1

Figure 1. Significance of the chiral lactams produced in this work is highlighted by the featured lactam-containing compounds.

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Chiral aryl lactams and their derivatives fulfill key roles as components of drugs and other bioactive natural products. (6) Furthermore, a review by Roughly and Jordan investigated the types of reactions employed in the pursuit of drug candidates; the category titled “heterocycle formation” was dominated by N-containing heterocycle syntheses. (7) Additionally, FDA databases disclose that approximately 60% of unique small-molecule drugs contain N-based heterocycles. (8) Categorically, δ-lactams have received less attention as potential drugs than β- and γ-lactams; (9) this presents an opportunity to develop more efficient methods to make them more accessible.
The synthetic strategy revealed in this work addresses a gap in desymmetrization and lactamization methodologies. While reports of lactamization techniques exist, (10−13) metal-free enantioselective lactamization methods are scarce. Reports of transition-metal-catalyzed reactions exist that take advantage of palladium, rhodium, iridium, cobalt, nickel, and molybdenum (see entry A, (14) Scheme 1 for an example). (15−19) Although metal-driven systems have accomplished impressive chemistry, metals are accompanied by challenges like high price, toxicity, pollution, waste treatment complications, and product contamination. (20) Thus, it is attractive to explore organocatalytic options. Sumiyoshi et al. built on nonselective methodologies (21) to synthesize chiral γ-lactams (22) (entry B, Scheme 1). When compound 8 was exposed to (S)-TRIP (50 mol %), γ-lactams (9) were fashioned with ee’s ranging from 49% to 66%. While modest ee’s are observed, a major limitation is the utilization of 0.5 equiv of the chiral phosphoric acid TRIP, which is impractical on a moderate to large scale. Additionally, a limited substrate scope is explored. In entry C (23) (Scheme 1), lactam 13 is prepared such that the stereocenter is previously established in precursor 12 before the heterocycle-forming step. While a chiral lactam is produced, its synthesis requires more than one step. Other published syntheses yield enantioenriched lactams, but the systems either are only diastereoselective (not enantioselective) (24) or do not contain a chiral center on the lactam ring. (25)

Scheme 1

Scheme 1. Literature Precedence, Other Lactamization Strategies, and Reaction Scheme for the Current Studya
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aTRIP = 3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate.

This study harnesses (R)-TRIP at only 5 mol % catalyst loading and produces δ-lactams with ee’s up to 75%. Our precursor amine 14 can be cyclized as a primary amine or secondary amine to yield lactam 15 (entry D, Scheme 1). The products contain substitution on the aromatic ring at the ortho, meta, and para positions with halogens, electron-donating groups, and electron-withdrawing groups. These enantioenriched lactams are synthesized in four steps; the concluding step is a metal-free desymmetrization catalyzed by the chiral Brønsted acid TRIP (3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate), a CPA catalyst. This desymmetrization is elegant because it simultaneously forms a benzo-fused δ-lactam while establishing an all-carbon quaternary chiral center and does not rely on transition-metal catalysts or previously set chiral centers. The remaining ester handle and select substituents on the aromatic ring allow for further functionalization. Besides the readily available starting materials and straightforward reaction conditions, another attractive feature is the ability to generate a vast number of substrates through variation of the nitrobenzyl bromide species, the R group at the α-carbon, and the use of primary or secondary aniline nitrogen nucleophiles. This current desymmetrization strategy was motivated by previous work in the Petersen group on the cyclization of hydroxy-esters to form lactones 17 (entry E, Scheme 1). (26,27) Though we draw inspiration from a previous strategy, we are excited to establish a new methodology to synthesize significantly more challenging nitrogen-based heterocycles.

Results and Discussion

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Malonate esters provide a scaffold to conduct desymmetrization reactions in the pursuit of chiral lactams (14 to 15, entry D, Scheme 1). Our general strategy began with the alkylation of di-tert-butyl malonate with bromide 18 (Scheme 2). A second alkyl group (e.g., via methyl iodide) is added to 19, giving the dialkylated product 20 (Scheme 2). The nitro group of 20 is hydrogenated to yield a free primary amine 14, which is poised to undergo an intramolecular cyclization reaction at a carbonyl carbon. We hypothesize that resonance with the aromatic ring moderates the reactivity of the nitrogen, allowing it to be an ideal nucleophile for this desymmetrization. Consult the Supporting Information for compound numbering details.

Scheme 2

Scheme 2. Synthetic Route to the Precursor Amines
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The optimization process began with evaluating the cyclization of aniline 14aa in the presence of various CPAs (Figure 2) to determine which CPA provided the best enantiomeric enrichment (Table 1, entries 1–7). Initial results indicated that catalyst 21a yielded the best enantioselectivity (50% ee, entry 1, Table 1) at 10 mol % and was utilized for evaluating all subsequent reaction variables. Other catalysts such as 21c, 21d, and 21e showed good reactivity but little enantioselectivity (Table 1, entries 3–5). Catalysts 21b, 21f, and 21g showed some enantioenrichment of product but lacked the desired reactivity (Table 1, entries 2, 6, and 7). It is known that modifying the BINOL backbone of the CPA can tune the electronics and solubility of the catalyst. (28,29) As seen in previous systems, this has various effects on experimental outcomes. (30,31)

Figure 2

Figure 2. Chiral phosphoric acid catalysts tested in the optimization process.

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Table 1. Reaction Optimization
entrycatalystcat. loadingsolventconcentration (M)temperature (°C)time (days)% eec% yieldb
1a21a10 mol %1,2-DCE0.025rt35098
221b10 mol %1,2-DCE0.025rt334 
321c10 mol %1,2-DCE0.025rt3289
421d10 mol %1,2-DCE0.025rt3790
521e10 mol %1,2-DCE0.025rt3034
621f10 mol %1,2-DCE0.025rt328 
721g10 mol %1,2-DCE0.025rt344d 
821a10 mol %hexanes0.025rt36199
921a10 mol %DCM0.025rt35575
1021a10 mol %bromobenzene0.025rt310 
1121a10 mol %toluene0.025rt36793
1221a10 mol %1,2-DCE0.025035583
1321a10 mol %1,2-DCE0.25rt35083
1421a10 mol %toluene0.25rt36398
1521a10 mol %toluene0.0025rt37299
16e21a5 mol %toluene0.0025rt37397
1721a5 mol %toluene0.025rt36997
1821a1 mol %toluene0.025rt36853
1921a1 mol %toluene0.0255036597
2021a1 mol %toluene0.0025rt76661
2121a5 mol %toluene, H2O/3 Å MS0.025rt52410
2221a5 mol %toluene, 3 Å MS0.025rt55625
2321a5 mol %toluene0.025–20103339
a

Base conditions: 10 mol % of 21a, 0.025 M in 1,2-DCE, stirring for 3 days at rt.

b

qNMR yields based on 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.

c

% ee values obtained via HPLC analysis.

d

Opposite enantiomer was formed per HPLC analysis.

e

Conditions giving the best results based first on % ee and then % yield. All optimization reactions conducted on a 10 mg scale. The full optimization table can be seen in the SI.

An examination of other nonpolar solvents (entries 8–11, Table 1) showed that toluene facilitated the best enantioenrichment, improving the ee of lactone 15aa from 50% to 67% (compare entries 1 and 11, Table 1). Hexanes (entry 8, Table 1) also performed favorably. We hypothesize that the hydrophobicity of these two solvents drives the substrate and the catalyst into closer proximity to interact more successfully. Polar solvents were not examined here after previous work within the group determined that polar solvents interfered with the binding abilities of 21a. (26,27)
Diluting the reaction concentration to 0.0025 M (with 10 mol % of 21a) improved the ee to 72% while still providing a yield of 99% (entry 15, Table 1). Lowering the catalyst loading to 5 mol % and concentration to 0.0025 M provided the best ee of 73% while maintaining a 97% yield (entry 16, Table 1). While comparable ee’s were achieved with a 1 mol % catalyst loading (entries 18 and 20, Table 1), yields suffered even when the reactions were allowed to run up to 7 days. However, it was discovered that heating the reaction to 50 °C with 1 mol % 21a enabled the reaction to run to completion with minimal decrease in ee (entry 19, Table 1). While we were able to salvage yield at 50 °C (entry 19), 5 mol % still offered better selectivity over 1 mol % (entries 16 and 17 vs entries 18–20) without requiring any heat and performed as well as 10 mol %, so we proceeded with the lower loading. Surprisingly, reducing the temperature to 0 °C (entry 12, Table 1) or subzero (entry 23, Table 1) did not improve the ee. In fact, −20 °C conditions resulted in remarkably lower ee and yield (entry 23, Table 1). The more dilute concentration afforded a slightly better ee (entries 15 and 16, Table 1). However, a 0.0025 M concentration is not convenient nor environmentally friendly on a practical scale. Therefore, while entry 16 afforded the best conditions technically (Table 1), the conditions that were used for the subsequent substrate scope were 0.025 M toluene with 5 mol % catalyst 21a at room temperature for 3 days.
DFT studies confirm a dual-binding activation mode (Figure 3), which occurs within a small “active site” where the substrate is engulfed by the bulky triisopropylphenyl groups. The Lewis base portion of 21a hydrogen bonds with an amine proton, while the Brønsted acid portion of 21a hydrogen bonds with the carbonyl oxygen of one of the esters (Figure 3a). These interactions intensify the nucleophilicity of the nitrogen and the electrophilicity of the carbonyl carbon. The Brønsted acid hydrogen (red) is concertedly transferred to the carbonyl oxygen as the C–N lactam bond is established. The triisopropylphenyl groups and the axial chirality of the catalyst direct the cyclization to occur in one preferred direction. The tetrahedral intermediate of the heterocycle collapses, producing a δ-lactam with a positively charged nitrogen. Finally, the abstraction of the hydrogen on the nitrogen (green) to regenerate the CPA catalyst is barrierless (Figure 3a). More detailed DFT calculations were conducted to examine the C–N bond-forming step for both enantiomers. Formation of the S enantiomer of 15aa follows a bidentate route, while the R enantiomer takes a monodentate route, leading to barrier heights of 9.89 and 16.74 kcal/mol for S and R, respectively (Figure 3b). These calculations demonstrate how the cyclization for the S enantiomer follows a more energetically favorable pathway than the R enantiomer. Full coordinates of this process are included in the Supporting Information. These data are consistent with previous DFT studies on similar desymmetrizations and kinetic resolutions. (32) All calculations were performed with the Gaussian 16 C01 package with ultrafine grids and tight self-consistent-field convergence. (33) Structures were optimized using the DFT M06-2X exchange-correlation energy density functional. (34) The basis set was triple-ζ 6-311+G(d) for N, O, and P elements and 6-31G(d) for C and H elements. (35) Toluene was the solvent included in the calculations with the CPCM (36) implicit solvent model employed.

Figure 3

Figure 3. (a) DFT and skeleton models of the transition state leading to the S enantiomer between 21a and 14aa, showing the concerted formation of the C–N lactam bond and the tetrahedral intermediate. (b) DFT model showing the bidentate binding of the transition state leading to the S enantiomer versus the monodentate binding of the transition state leading to the R enantiomer

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We embarked on the substrate scope with the intent of showcasing the method’s versatility. Various alkylating groups and aryl electron-withdrawing groups and electron-donating groups were tested to determine what complimented or inhibited the system (Figure 4). The reactivity and resultant ee’s were not significantly impacted by the electronics of the various groups on the aniline ring. Substituents at the meta and para positions to the amine on the aromatic ring do not affect the efficacy of the reaction (15cb–15fa, Figure 4). We hypothesize that substrate 15ba suffered lower enantioenrichment due to steric interference of the ortho-methyl group on the amine.

Figure 4

Figure 4. Scope of lactam substrates produced. Consult the Supporting Information for more detail.

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Generally, any alkyl moiety at the α-carbon was well tolerated. Bulkier groups like an isopropyl or sec-butyl (15ac and 15ad, Figure 4) can be attached without significant negative impacts being observed. The presence of the heteroatom in the alkylating chain (at the α-carbon) resulted in a significantly lower ee (23%), while a high yield (96%) was retained (15af). We theorize that the oxygen atom interrupts the hydrogen bonding network between catalyst and substrate. We validated that the di-tert-butyl esters were optimal for cyclization by preparing the less bulky diisopropyl ester. Upon hydrogenating the dialkylated diisopropyl malonate to the amine, a sizable portion cyclized spontaneously in situ to form the racemic lactam (23aa). Uncyclized amine underwent spontaneous cyclization, even when material was stored at 4–5 °C. We then prepared and cyclized secondary amines to manufacture lactams with a methylated nitrogen (Figure 4, compound 22aa). The synthetic route to the secondary amines was analogous to that of the primary amines. We were excited to produce 22aa with 75% ee from a secondary amine subjected to 5 mol % 21a. Consult Scheme S1 in the SI for the full synthetic route.
The absolute configuration of lactam 15aa was determined to be S via X-ray crystallography. All other lactams were assigned based on analogy. Consult the SI for details on the crystal growth method.
Moreover, we can show that recrystallization of lactams leads to improved enantioenrichment with satisfactory recovery of mass. Several recrystallization attempts were conducted (entries 1–6, Table 2) before obtaining crystals with 87% ee in 60% recovery (entry 6, Table 2). The enantioselective recrystallization was an exercise in balance; some entries provided excellent ee with very poor recovery (entry 3), while others had good recovery but only marginally improved the ee (entry 4). Fortunately, in all cases, we could reconcentrate the mother liquor to recover all of the material to attempt a better recrystallization. We felt that 0.43 g of crystals with 87% ee was satisfactory. These results do show, however, that it is possible to obtain enantiomerically pure crystals.
Table 2. Summary of Results from Recrystallization Study
entrystarting mass (g)starting eerecovered mass (g)% recoveryee of recrystallization
10.7664%0.1723%91%
20.7464%0.4865%72%
30.7364%0.033.5%98%
40.7364%0.6691%70%
50.7264%0.4968%78%
60.7264%0.4360%87%
Additionally, while the reactions for the substrate scope (Figure 4) were performed on a 100 mg scale with 5 mol % 21a, our method can be adapted to larger scale (>1 g) with lower catalyst loading (2 mol % 21a). The model substrate 14aa was subjected to a cyclization in toluene at 0.025 M at 50 °C with 2 mol % 21a. This large-scale lactamization gave 15aa in 96% yield and 75% ee (1.05 g, 4.00 mmol) from 1.40 g (4.17 mmol) of 14aa, as depicted in Scheme 3.

Scheme 3

Scheme 3. Large-Scale Cyclization Using Decreased Catalyst Loading
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To demonstrate the applicability and practical usefulness of the chiral lactam products, we have conducted further manipulations on select substrates (Scheme 4). These transformations are relevant because they can expand the molecule so that it fits the needs of specific targets or can emulate valuable bioactive motifs. The remaining ester moiety in compound 15aa can be reduced to yield an aldehyde 26, or the lactam can be further reduced to give a 6-membered amine heterocycle 27. Alternatively, incorporation of a halogen in the aniline ring as seen in substrates 15ea and 15eb allows for potential coupling reactions. Highlighting this use, we were able to perform a Suzuki–Miyaura coupling (37) of 15ea and 4-tolylboronic acid to produce 28 in 56% yield as shown in Scheme 4.

Scheme 4

Scheme 4. Substrates Can Be Further Manipulated To Increase Complexity and Adjust Chemical Properties
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Conclusion

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We have reported an elegant methodology to synthesize benzo-fused δ-lactams in yields up to 96% and enantiomeric excess up to 75% through the desymmetrization of disubstituted malonic esters in the presence of a chiral Brønsted acid organocatalyst. Benzo-fused δ-lactams are seen in an array of valuable compounds; accessing this motif through our methodology will significantly aid in the ability to synthesize these compounds or necessary analogues. To the best of our knowledge, this is the first enantioselective Brønsted acid-catalyzed lactamization resulting in benzo-fused δ-lactams. Properly harnessing nitrogen as a nucleophile is challenging; nitrogen can be nonreactive, too basic (deprotonating the catalyst and killing reaction), or too nucleophilic (attacking the carbonyl too rapidly and foregoing selectivity). We found that an aniline nitrogen maintained a satisfactory balance between nucleophilicity and reactivity. The substrate scope allows for diversification in structure, which lends to variation in how each lactam can be subsequently utilized. Both primary and secondary amines can successfully complex with TRIP to produce enantioenriched δ-lactams and N-methylated δ-lactams. The substrates can be further manipulated via reductions or a coupling reaction. This lactamization strategy can also be scaled up; merely 2 mol % 21a can achieve 75% ee and 96% yield on a >1 g scale. We expect that the work reported will provide a facile and efficient means for chemists to produce desired molecules.

Experimental Details

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General Methods

Unless noted, all solvents and reagents were obtained from commercial sources and used without further purification; anhydrous solvents were dried following standard procedures. Compounds 18a–18e were purchased from a chemical supplier (1PlusChem, TCI, Sigma-Aldrich, or Chemcia Scientific, LLC); compound 18f was synthesized by brominating 5-methoxy-2-nitrotoluene (please consult the Supporting Information for a full compound numbering guide). Purity and identity analysis was conducted on compound 18b. The 1H and 13C (proton decoupled) nuclear magnetic resonance (NMR) spectra were plotted on a 400 MHz spectrometer using CDCl3 and acetone-d6 as solvents at room temperature. The NMR chemical shifts (δ) are reported in parts per million. Abbreviations for 1H NMR: s = singlet, d = doublet, m = multiplet, br s = broad singlet, t = triplet, q = quartet, sept = septet, hept = heptet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, dq = doublet of quartets. The reactions were monitored by TLC using silica G F254 precoated plates. Flash chromatography was performed using flash-grade silica gel (particle size 40–63 μm, 230 × 400 mesh). Enantiomeric excess was determined by HPLC analysis. High-resolution mass spectra were acquired on an Orbitrap XL MS system. The specific rotations were acquired on an analytical polarimeter.

General Method for Quantitative NMR

1H NMR was used to quantify yields for the optimization table reactions (10 mg scale). After the cyclization reaction of amine 14aa with catalyst 21a, the reaction mixture was concentrated. Crude lactam 15aa was diluted with CDCl3 and added to an NMR tube. An internal standard solution of 1,3,5-trimethoxybenzene in CDCl3 was prepared. A known amount of internal standard solution was added to the NMR tube containing product 15aa. The most shielded aromatic peak of 15aa was compared to the aromatic singlet of the internal standard. Stoichiometric calculations in an Excel spreadsheet revealed the percent yield based on the integrations of the peaks, how many protons each peak represented, and theoretical yield for each specific reaction and spectrum.

Compound 18b

To verify the identity and purity of the brominated nitrotoluene species purchased commercially (Chemcia Scientific, LLC; CAS no. 55324-02-2), 18b was characterized according to 1H NMR, 13C{1H} NMR, HRMS, and melting point. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H), 7.26 (m, 1H), 4.46 (s, 2H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.7, 132.0, 131.0, 130.8, 129.8, 129.1, 27.0, 17.8; mp = 55.2–56.5 °C. HRMS (ESI) m/z: [M + H]+ calcd 229.9811 for C8H8BrNO2; found 229.9818.

Compound 18f

To a flame-dried flask were added 5-methoxy-2-nitrotoluene (3.1 g, 18 mmol) and n-bromosuccinimide (3.6 g, 20 mmol) under argon. Benzene (50 mL) was then added to the flask, followed by azobisisobutyronitrile (0.45 g, 2.7 mmol). The solution was stirred at 90 °C for 4 h with a reflux condenser attached. The reaction was cooled to room temperature and filtered through a silica plug with excess hexanes. The organic material was concentrated. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 18f as a light-yellow oil (1.4 g, 31% yield). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.3 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 9.1, 2.8 Hz, 1H), 4.86 (s, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.6, 140.8, 135.9, 128.6, 117.7, 114.2, 56.2, 30.1. Characterization data matches previously reported data. (38)

Compound 19a

To a solution of sodium hydride (60% dispersion in mineral oil, 0.57 g, 14 mmol) in dimethylformamide (30 mL) in a flame-dried flask was added di-tert-butyl malonate (2.7 mL, 12 mmol) at 0 °C under argon. The solution was stirred for several minutes to allow for gas evolution. To the solution at 0 °C was added 18a (2.5 g, 11 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 30 mL of a 1:1 ratio of ammonium chloride and water and was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 19a as a light yellow oil (3.8 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2 H), 3.62 (t, J = 7.8 Hz, 1H), 3.39 (d, J = 8.0 Hz, 2H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.0, 149.3, 133.7, 133.3, 133.2, 128.1, 125.2, 81.9, 53.9, 32.2, 27.9. HRMS (ESI) m/z: [M + H]+ calcd 352.1755 for C18H25NO6; found 352.1713.

Compound 19b

To a solution of sodium hydride (60% dispersion in mineral oil, 0.17 g, 4.4 mmol) in dimethylformamide (8 mL) in a flame-dried flask was added di-tert-butyl malonate (0.52 mL, 2.4 mmol) at 0 °C under argon. The solution was stirred for several minutes to allow for gas evolution. To the solution at 0 °C was added 18b (0.49 g, 2.2 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 8 mL of a 1:1 ammonium chloride and water solution and was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 19b as a light yellow oil (0.72 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 7.16 (m, 2H), 3.51 (t, J = 7.8 Hz, 1H), 3.09 (d, J = 7.8 Hz, 2H), 2.30 (s, 3 H), 1.40 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 151.9, 147.0, 130.1, 130.02, 129.95, 128.8, 82.1, 54.2, 30.2, 27.9, 17.7. HRMS (ESI) m/z: [M + Na]+ calcd 388.1730 for C19H27NO6Na; found 388.1724.

Compound 19c

To a solution of sodium hydride (60% dispersion, 170 mg, 4.3 mmol) in DMF (7 mL) in a flame-dried round-bottom flask was added di-tert-butyl malonate (0.49 mL, 2.4 mmol) at 0 °C under argon. After the ceasing of gas evolution, 18c was added (500 mg, 2.1 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 8 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (20% → 100% EtOAc in hexanes) to afford compound 19c as a light-yellow oil (740 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 1H), 7.33 (m, 1H), 3.55 (t, J = 7.7 Hz, 1H), 3.46 (d, J = 7.9 Hz, 2H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.6, 160.3, 128.5, 122.1, 120.7, 120.3, 81.8, 53.1, 27.8, 23.8; 19F NMR (376 MHz, CDCl3) δ −110.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd 370.1660 for C18H24FNO6; found 370.1656.

Compound 19e

To a solution of sodium hydride (60% dispersion, 320 mg, 7.9 mmol) in DMF (14 mL) in a flame-dried round-bottom flask was added di-tert-butyl malonate (0.96 mL, 4.4 mmol) at 0 °C under argon. The solution was stirred for several minutes to allow for gas evolution. To the solution at 0 °C was added 18e (1.0 g, 3.9 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 14 mL of a 1:1 ammonium chloride and water solution and was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 19e as a white, fluffy solid (1.2 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.5, 2.4 Hz, 1H), 3.62 (t, J = 7.8 Hz, 1H), 3.38 (d, J = 7.6 Hz, 2H), 1.40 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.7, 147.4, 139.5, 135.8, 133.1, 128.2, 126.7, 82.2, 53.7, 32.1, 27.9; mp = 74.1–76.6 °C. HRMS (ESI) m/z: [M + Na]+ calcd 408.1184 for C18H24ClNO6Na; found 408.1181.

Compound 31a

To a solution of sodium hydride (60% dispersion, 560 mg, 14 mmol) in DMF (24 mL) in a flame-dried round-bottom flask was added diisopropyl malonate (1.7 mL, 8.7 mmol) at 0 °C under argon. The solution was stirred for several minutes to allow for gas evolution. To the solution at 0 °C was added 18a (1.5 g, 6.9 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 24 mL of a 1:1 ammonium chloride and water solution and was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 31a as a light-yellow oil (1.9 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 4.95 (sept, J = 6.4 Hz, 2H), 3.74 (t, J = 7.8 Hz, 1H), 3.43 (d, J = 7.7 Hz, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.10 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.2, 149.2, 133.3, 133.3, 133.2, 128.2, 125.2, 69.3, 52.6, 32.1, 21.6. HRMS (ESI) m/z: [M + H]+ calcd 324.1439 for C16H21NO6; found 324.1442.

Compound 20da

To a solution of sodium hydride (60% dispersion, 140 mg, 3.5 mmol) in dry THF (10 mL) were slowly added di-tert-butyl 2-methylmalonate (0.45 mL, 1.9 mmol) followed by 18d (500 mg, 1.7 mmol) at 0 °C. The reaction was allowed to warm to 21 °C and stirred for 16 h under argon. The reaction was cooled to 0 °C, quenched with 10 mL of a 1:1 10% HCl and water solution, and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (1% → 15% EtOAc in hexanes) to afford compound 20da as a colorless oil (490 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.72 (d, J = 8.24 Hz, 1H), 7.65 (d, J = 8.24 Hz, 1H), 3.61 (s, 2H), 1.41 (s, 18H), 1.26 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 150.7, 136.6, 134.3, 130.5 (q, J = 34.5 Hz), 128.7, 124.3, 122.0, 82.2, 56.1, 35.9, 28.0, 20.5 ppm; 19F NMR (376 MHz, CDCl3) δ 62.8 ppm. HRMS (ESI) m/z: [M + H]+ calcd 434.1785 for C20H26F3NO6; found 434.1791.

Compound 20fa

To a solution of sodium hydride (60% dispersion, 350 mg, 8.6 mmol) in dry THF (35 mL) were slowly added di-tert-butyl 2-methylmalonate (1.6 g, 6.8 mmol) followed by 18f (1.4 g, 5.7 mmol) at 0 °C. The reaction was allowed to warm to 21 °C and stirred for 16 h under argon. The reaction was cooled to 0 °C, quenched with 30 mL of a 1:1 1 M HCl and water solution, and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (5% → 15% EtOAc in hexanes) to afford compound 20fa as a white powdery solid (1.2 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 9.2, 2.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 2H), 1.42 (s, 18H), 1.25 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 162.6, 143.8, 135.6, 127.6, 118.4, 112.5, 81.8, 56.3, 55.9, 36.3, 27.9, 20.1 ppm; mp = 67.2–68.4 °C. HRMS (ESI) m/z: [M + H]+ calcd 396.2017 for C20H29NO7; found 396.2007.

Compound 20aa

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 370 mg, 9.2 mmol) in DMF (12 mL) was made. Compound 19a (1.6 g, 4.6 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, methyl iodide was added (0.36 mL, 5.8 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20aa as a clear, pale-yellow oil (1.5 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.44 (m, 2H), 7.35 (t, J = 7.4 Hz, 1H), 3.58 (s, 2H), 1.41 (s, 18H), 1.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 151.0, 133.1, 132.3, 132.1, 127.8, 124.7, 81.2, 56.1, 35.7, 27.9, 20.0. HRMS (ESI) m/z: [M + Na]+ calcd 388.1730 for C19H27NO6Na; found 388.1724.

Compound 20ab

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 110 mg, 7.8 mmol) in DMF (13 mL) was made. Compound 19a (1.5 g, 4.3 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, ethyl iodide was added (1.2 mL, 3.9 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 14 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ab as a light-yellow powder (1.4 g, 92% yield). 20ab was taken on to the next step without characterization (see compound 14ab).

Compound 20ac

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 320 mg, 7.9 mmol) in THF (30 mL) was made. Compound 19a (2.2 g, 6.3 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, 2-iodopropane was added (1.3 mL, 13 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 30 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ac as a clear, pale-yellow oil (1.7 g, 69% yield). 20ac was taken on to the next step without characterization (see compound 14ac).

Compound 20ad

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 290 mg, 6.3 mmol) in DMF (20 mL) was made. Compound 19a (1.1 g, 3.1 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, 1-bromo-2-methylpropane was added (0.60 mL, 3.8 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 20 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (2% → 20% EtOAc in hexanes) to afford compound 20ad as a pale-yellow oil (780 mg, 61% yield). 20ad was taken on to the next step without characterization (see compound 14ad).

Compound 20ae

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 310 mg, 7.7 mmol) in DMF (13 mL) was made. Compound 19a (1.3 g, 3.9 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, benzyl bromide was added (0.55 mL, 4.6 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 14 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate three times (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ae as a clear, yellow oil (1.4 g, 87% yield). 20ae was taken on to the next step without characterization (see compound 14ae).

Compound 20af

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 230 mg, 5.7 mmol) in DMF (10 mL) was made. Compound 19a (1.0 g, 2.9 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, 1-bromo-3-methoxypropane was added (0.35 mL, 3.1 mmol). The reaction was stirred at 40 °C under argon gas for 16 h. The reaction was quenched with 10 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20af as a yellow oil (1.1 g, 90% yield). 20af was taken on to the next step without characterization (see compound 14af).

Compound 20ba

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 160 mg, 3.9 mmol) in DMF (10 mL) was made. Compound 19b (710 mg, 1.9 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, methyl iodide was added (0.13 mL, 2.1 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 10 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ba as a clear, pale-yellow oil (650 mg, 88% yield). 20ba was taken on to the next step without characterization (see compound 14ba).

Compound 20cb

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 140 mg, 3.4 mmol) in DMF (8 mL) was made. Compound 19c (510 mg, 1.4 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, ethyl iodide was added (0.22 mL, 2.7 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 8 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate three times (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20cb as a yellow oil (430 mg, 80% yield). 20cb was taken on to the next step without characterization (see compound 14cb).

Compound 20ea

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 250 mg, 6.2 mmol) in DMF (12 mL) was made. Compound 19e (1.2 g, 3.1 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, methyl iodide was added (0.21 mL, 3.4 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ea as a clear, yellow oil (1.1 g, 86% yield). 20ea was taken on to the next step without characterization (see compound 14ea).

Compound 20eb

To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 230 mg, 5.6 mmol) in DMF (12 mL) was made. Compound 19e (1.1 g, 2.8 mmol) was then added slowly at 0 °C. After the ceasing of gas evolution, ethyl iodide was added (1.1 mL, 3.4 mmol). The reaction was stirred at 40 °C under argon for 16 h. The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (5% → 30% EtOAc in hexanes) to afford compound 20eb as a clear, yellow oil (790 mg, 68% yield). 20eb was taken on to the next step without characterization (see compound 14eb).

Compound 32aa

To a solution of sodium hydride (60% dispersion, 0.47 g, 12 mmol) in DMF (20 mL) in a flame-dried dried round-bottom flask was added compound 31a (1.9 g, 5.9 mmol) at 0 °C under argon. The solution was stirred for several minutes to allow for gas evolution. To the solution at 0 °C was added methyl iodide (0.40 mL, 6.5 mmol). The solution was warmed to 21 °C, transferred to an oil bath set to 40 °C, and stirred for 16 h. The reaction was quenched with 24 mL of a 1:1 ammonium chloride and water solution and was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% → 100% EtOAc in hexanes) to afford compound 32aa as a yellow oil (1.5 g, 77% yield). 32aa was confirmed via 1H NMR and 13C NMR and then taken on to the next step without further characterization (see compound 33aa). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 4.99 (hept, J = 6.2 Hz, 2H), 3.63 (s, 2H), 1.26 (s, 3H), 1.19 (t, J = 6.5 Hz, 12 H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 150.9, 133.1, 132.4, 131.6, 128.0, 124.8, 69.3, 54.9, 35.9, 21.6, 19.9.

Compound 14aa

To a solution of compound 20aa (2.0 g, 5.5 mmol) in ethyl acetate (30 mL) was added Pd(OH)2/C (340 mg, 2.5 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (20 mL). The ethyl acetate solution was concentrated in vacuo. The light-yellow solid was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14aa as a white crystalline solid (1.5 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 6.93 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 4.52 (s, 2H), 1.42 (s, 18H), 1.28 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 147.1, 131.8, 127.5, 120.6, 116.8, 115.6, 80.8, 56.0, 35.1, 27.2, 19.8; mp = 70.9–72.2 °C. HRMS (ESI) m/z: [M + H]+ calcd 336.2169 for C19H29NO4; found 336.2165.

Compound 14ab

To a solution of compound 20ab (340 mg, 0.89 mmol) in ethyl acetate (3.0 mL) was added Pd(OH)2/C (50 mg, 0.36 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas five times. The reaction proceeded at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (10 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (10% → 100% EtOAc in hexanes) to afford compound 14ab as a white powder (300 mg, 96% yield). 1H NMR (400 MHz, C3D6O) δ 6.90 (m, 2H), 6.64 (d, J = 8.5 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 3.00 (s, 2H), 1.88 (q, J = 7.4 Hz, 2H), 1.37 (s, 18H), 0.88 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, C3D6O) δ 170.9, 147.1, 131.5, 127.3, 121.1, 116.8, 115.5, 80.8, 59.8, 32.3, 27.1, 26.8, 8.2; mp = 88–91 °C. HRMS (ESI) m/z: [M + H]+ calcd 350.2326 for C20H31NO4; found 350.2328.

Compound 14ac

To a solution of compound 20ac (1.3 g, 3.2 mmol) in ethyl acetate (30 mL) was added Pd(OH)2/C (180 mg, 1.3 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (20 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14ac as a light-yellow oil (720 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6, 1H), 6.62 (t, J = 7.6, 2H), 3.09 (s, 2H), 2.45 (sept, J = 6.7 Hz, 1H), 1.28 (s, 18H), 1.06 (d, J = 6.8, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 145.7, 132.5, 127.6, 123.5, 118.5, 116.3, 81.5, 63.8, 35.7, 34.1, 27.8, 18.9. HRMS (ESI) m/z: [M + H]+ calcd 364.2482 for C21H33NO4; found 364.2472.

Compound 14ad

To a solution of compound 20ad (110 mg, 0.26 mmol) in ethyl acetate (6 mL) was added Pd(OH)2/C (18 mg, 0.13 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (25 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (10 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14ad as a light-yellow oil (95 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ 7.00 (t, J = 8.7 Hz, 2H), 6.75 (dt, J = 14.9, 8.3 Hz, 2H), 3.12 (s, 2H), 1.96 (d, J = 6.3 Hz, 2H), 1.78 (sept, J = 6.5 Hz, 1H), 1.31 (s, 18H), 0.94 (d, J = 6.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 144.5, 132.3, 127.8, 123.4, 119.2, 116.9, 81.9, 59.7, 44.8, 34.7, 27.9, 24.6, 24.3. HRMS (ESI) m/z: [M + H]+ calcd 378.2639 for C22H35NO4; found 378.2645.

Compound 14ae

To a solution of compound 20ae (7.2 g, 16 mmol) in ethyl acetate (50 mL) was added Pd(OH)2/C (910 mg, 6.5 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (25 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (15 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14ae as a light-yellow oil (4.3 g, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 5H), 7.07 (d, J = 7.9, 1H), 6.99 (t, J = 7.3, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 3.35 (s, 2H), 3.03 (s, 2H), 1.32 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 145.6, 136.7, 131.6, 130.3, 128.2, 127.6, 126.9, 122.3, 118.4, 116.2, 82.0, 60.2, 41.4, 34.3, 27.8. HRMS (ESI) m/z: [M + H]+ calcd 412.2482 for C25H33NO4; found 412.2479.

Compound 14af

To a solution of compound 20af (1.1 g, 2.6 mmol) in ethyl acetate (9 mL) was added Pd(OH)2/C (180 mg, 1.3 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (15 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14af as a light-yellow solid (890 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ6.98 (t, J = 7.2 Hz, 2H), 6.64 (t, J = 7.1 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H), 3.30 (s, 3H), 3.07 (s, 2H), 1.94 (m, 2H), 1.55 (dq, J = 11.1, 6.7 Hz, 2H), 1.34 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ171.4, 145.3, 132.3, 127.8, 122.2, 118.6, 116.5, 81.7, 72.8, 59.9, 58.6, 33.9, 31.9, 27.8, 24.6; mp = 81.3–82.4 °C. HRMS (ESI) m/z: [M + H]+ calcd 394.2588 for C22H35NO5; found 394.2583.

Compound 14ba

To a solution of compound 20ba (650 mg, 1.7 mmol) in ethyl acetate (6 mL) was added Pd(OH)2/C (120 mg, 0.86 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (10 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (10 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14ba as a yellow oil (370 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 7.3 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.62 (t, J = 7.4 Hz, 1H), 3.11 (s, 2H), 2.18 (s, 3H), 1.41 (s, 18H), 1.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 142.7, 130.3, 129.3, 123.4, 121.7, 118.4, 81.7, 56.1, 36.0, 28.0, 21.0, 18.4. HRMS (ESI) m/z: [M + H]+ calcd 350.2326 for C20H31NO4; found 350.2325.

Compound 14cb

To a solution of compound 20cb (430 mg, 1.1 mmol) in ethyl acetate (4 mL) was added Pd(OH)2/C (60 mg, 0.44 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas five times. The reaction proceeded at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (10 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (10% → 100% EtOAc in hexanes) to afford compound 14cb as a light-yellow powder (280 mg, 69% yield). 1H NMR (400 MHz, C3D6O) δ 6.90 (q, J = 7.5 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 6.25 (t, J = 8.9 Hz, 1H), 3.05 (s, 2H), 1.93 (q, J = 7.5 2H), 1.33 (s, 18H), 0.90 (t, J = 7.8 Hz, 3H); 13C{1H} NMR (100 MHz, C3D6O) δ 171.0, 163.0 (d, J = 240.0 Hz), 149.8 (d, J = 7.3 Hz), 128.3 (d, J = 11.1 Hz), 110.8, 109.1 (d, J = 18.6 Hz), 102.7 (d, J = 24.0 Hz), 81.1, 59.6, 27.0, 26.6, 8.1; 19F NMR (376 MHz, (CD3)2CO) δ −114.4 ppm; mp = 60–63 °C. HRMS (ESI) m/z: [M + H]+ calcd 368.2232 for C20H30FNO4; found 368.2222.

Compound 14da

To a solution of compound 20da (490 mg, 1.1 mmol) in ethyl acetate (5 mL) was added Pd(OH)2/C (80 mg, 0.57 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times, after which the reaction was stirred at 21 °C under hydrogen for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (10 mL). The ethyl acetate solution was concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (10% → 25% EtOAc in hexanes) to afford compound 14da as a white solid (390 mg, 87% yield). 1H NMR (400 MHz, (CD3)2CO) δ 7.13 (d, J = 7.8 Hz, 1H), 6.98 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.05 (br s, 2H), 3.09 (s, 2H), 1.42 (s, 18H), 1.30 (s, 3H) ppm; 13C{1H} NMR (100 MHz, (CD3)2CO) δ 171.9, 148.7, 133.2, 130.1 (q, J = 31.6 Hz), 125.4, 124.2, 113.3, 112.2, 81.9, 56.7, 35.7, 28.0, 20.6 ppm; 19F NMR (376 MHz, (CD3)2CO) δ 63.5 ppm; mp = 64.3–65.6 °C. HRMS (ESI) m/z: [M + H]+ calcd 404.2043 for C20H28F3NO4; found 404.2036.

Compound 14ea

To a solution of compound 20ea (1.7 g, 4.2 mmol) in ethyl acetate (17 mL) was added Pd(OH)2/C (240 mg, 1.7 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (20 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (20 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14ea as a thick dark orange oil (930 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 8.8 Hz, 2H), 6.52 (dd, J = 8.4, 1.9 Hz, 1H), 4.06 (s, 2H), 3.00 (s, 2H), 1.39 (s, 18H), 1.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.7, 144.5, 131.7, 127.7, 123.2, 122.5, 117.3, 81.9, 56.1, 35.6, 27.9, 21.0. HRMS (ESI) m/z: [M + H]+ calcd 370.1780 for C19H28ClNO4; found 370.1786.

Compound 14eb

To a solution of compound 20eb (130 mg, 0.31 mmol) in ethyl acetate (5 mL) was added Pd(OH)2/C (17 mg, 0.12 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (10 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (15 mL). The ethyl acetate solution was concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (15% → 40% EtOAc in hexanes) to afford compound 14eb as a thick yellow oil (76 mg, 64% yield). 1H NMR (400 MHz, (CD3)2CO) δ 6.94 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 4.72 (br s, 2H), 2.99 (s, 2H), 1.88 (q, J = 7.6 Hz, 2H), 1.38 (s, 18H), 0.89 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 170.7, 146.3, 130.9, 127.1, 123.1, 120.6, 116.8, 81.1, 60.0, 32.4, 27.3, 27.2, 8.2. HRMS (ESI) m/z: [M + H]+ calcd 384.1936 for C20H30ClNO4; found 384.1925.

Compound 14fa

To a solution of compound 20fa (1.1 g, 2.7 mmol) in ethyl acetate (12 mL) was added Pd(OH)2/C (160 mg, 1.1 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times, after which the reaction was stirred at 21 °C under hydrogen for 18 h. The reaction was diluted with ethyl acetate, passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (15 mL). The ethyl acetate solution was concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (20% → 40% EtOAc in hexanes) to afford compound 14fa as a dark-purple solid (570 mg, 57% yield). 1H NMR (400 MHz, (CD3)2CO) δ 6.64 (d, J = 8.7 Hz, 1H), 6.59 (m, 2H), 4.16 (br s, 2H), 3.65 (s, 3H), 3.05 (s, 2H), 1.46 (s, 18H), 1.31 (s, 3H) ppm; 13C{1H} NMR (100 MHz, (CD3)2CO) δ 172.2, 152.7, 141.6, 123.2, 118.2, 117.6, 114.0, 81.7, 56.9, 55.8, 36.0, 28.1, 20.5 ppm; mp = 58.8–60.1 °C. HRMS (ESI) m/z: [M + H]+ calcd 366.2275 for C20H31NO5; found 366.2265.

Compound 24aa

To a solution of sodium hydride (60% dispersion, 14 mg, 0.35 mmol) and anhydrous DMF (10 mL) in a flame-dried round-bottom flask was added 14aa (0.12 g, 0.35 mmol) at 21 °C. The reaction stirred for 10 min before methyl iodide (0.01 mL, 0.15 mmol) was added dropwise. The reaction stirred for 18 h at 21 °C before being quenched with 10 mL of saturated ammonium chloride and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The yellow liquid was purified by flash chromatography (10% → 50% EtOAc in hexanes) to afford compound 24aa as a viscous yellow oil (55 mg, 45% yield). 1H NMR (400 MHz, (CD3)2CO) δ 7.04 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.50 (m, 2H), 4.79 (br s, 1H), 3.02 (s, 3H), 2.76 (d, J = 5.2 Hz, 3H), 1.41 (s, 18H), 1.25 (s, 3H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 171.4, 148.5, 131.5, 127.9, 120.9, 115.7, 109.7, 80.8, 55.9, 34.9, 29.9, 27.2, 19.8. HRMS (ESI) m/z: [M + H]+ calcd 350.2326 for C20H31NO4; found 350.2313.

Compound 33aa

To a solution of compound 32aa (0.36 g, 1.0 mmol) in ethyl acetate (4 mL) was added Pd(OH)2/C (66 mg, 0.47 mmol) at 21 °C. The solution was degassed and purged with hydrogen gas three times. The reaction was stirred at 21 °C under hydrogen gas for 18 h. The reaction was diluted with ethyl acetate (15 mL), passed through a silica plug to remove Pd(OH)2/C, and rinsed with additional ethyl acetate (20 mL). The ethyl acetate solution was concentrated in vacuo. The yellow liquid was purified by flash chromatography on silica gel (15% → 45% EtOAc in hexanes) to afford compound 33aa as a thick yellow oil (31 mg, 9% yield). Most of the isolated material was the lactam (see 23aa). 1H NMR (400 MHz, (CD3)2CO) δ 6.90 (m, 2H), 6.65 (d, J = 7.8 Hz, 1H), 6.50 (t, J = 7.4, 1H), 4.95 (hept, J = 6.2 Hz, 2H), 4.51 (br s, 1H), 3.09 (s, 2H), 1.32 (s, 3H), 1.20 (d, J = 6.5 Hz, 6H), 1.17 (d, J = 6.5 Hz, 6H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 171.5, 147.1, 131.6, 127.6, 120.3, 116.9, 115.7, 68.6, 54.9, 35.2, 21.0, 20.9, 19.4. HRMS (ESI) m/z: [M + H]+ calcd 308.1856 for C17H25NO4; found 308.1845.

Compound 15aa

To a solution of compound 14aa (110 mg, 0.32 mmol) in dry toluene (13 mL, 0.025 M) in a flame-dried two-neck round-bottom flask was added 21a (12 mg, 0.016 mmol) at 21 °C. The reaction was stirred at 21 °C under argon for 3 days. The reaction was quenched with 14 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20% → 100% EtOAc in hexanes) to afford compound 15aa as a white fluffy solid (81 mg, 96% yield, 71% ee). 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 3.26 (d, J = 15.7, Hz, 1H), 2.86 (d, J = 15.6 Hz, 1H), 1.48, (s, 3H) 1.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 171.2, 137.1, 128.2, 127.8, 123.2, 122.7, 115.0, 82.2, 50.1, 37.7, 27.6, 20.0; mp = 98.1–99.9 °C. HRMS (ESI) m/z: [M + H]+ calcd 262.1438 for C15H19NO3; found 262.1435. [α]D21 = +20.60 (c = 0.5, CHCl3).

Compound 15ab

To a solution of compound 14ab (100 mg, 0.29 mmol) in dry toluene (11 mL, 0.025 M) was added 21a (11 mg, 0.014 mmol) at 21 °C. The solution was stirred at 50 °C under argon for 6 days. The reaction was quenched with 12 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (10% → 100% EtOAc in hexanes) to afford compound 15ab as a white powder (70 mg, 89% yield, 70% ee). 1H NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H), 7.15 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 3.19 (d, J = 15.5, 1H), 2.94 (d, J = 16.2 Hz, 1H), 1.97 (m, 2H), 1.23 (s, 9H), 1.03 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 170.4, 136.6, 128.2, 127.6, 123.2, 123.0, 115.0, 82.1, 54.0, 33.9, 27.5, 26.3, 9.3; mp = 73–75 °C. HRMS (ESI) m/z: [M + H]+ calcd 276.1594 for C16H21NO3; found 276.1514. [α]D21 = +11.48 (c = 0.5, CHCl3).

Compound 15ac

To a solution of compound 14ac (100 mg, 0.31 mmol) in dry toluene (13 mL, 0.025 M) was added 21a (11 mg, 0.015 mmol) at 21 °C. The reaction was stirred at 50 °C under argon for 7 days. The reaction was quenched with 12 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15ac as a white powdery solid (70 mg, 94% yield, 50% ee). 1H NMR (400 MHz, CDCl3) δ 7.64 (br s, 1H), 7.16 (m, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 3.10 (d, J = 15.5 Hz, 1H), 2.97 (d, J = 15.4 Hz, 1H), 2.60 (sept, J = 6.9 Hz, 1H), 1.22 (s, 9H), 1.11 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 169.6, 136.3, 128.5, 127.6, 123.8, 123.3, 114.6, 82.2, 57.5, 31.5, 30.9, 19.0, 17.8 ppm; mp = 129.4–134.8 °C. HRMS (ESI) m/z: [M + H]+ calcd 290.1751 for C17H23NO3; found 290.1745. [α]D21 = +1.93 (c = 0.5, CHCl3).

Compound 15ad

To a solution of compound 14ad (120 mg, 0.35 mmol) in dry toluene (14 mL, 0.025 M) in a flame-dried two-neck round-bottom flask was added 21a (13 mg, 0.017 mmol) at 21 °C. The reaction was stirred at 21 °C under argon for 6 days. The reaction was quenched with 14 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20% → 100% EtOAc in hexanes) to afford compound 15ad as a light-yellow solid (82 mg, 85% yield, 55% ee). 1H NMR (400 MHz, CDCl3) δ 8.52 (br s, 1H), 7.15 (t, J = 7.8 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 3.25 (d, J = 15.6 Hz, 1H), 2.96 (d, J = 15.7 Hz, 1H), 1.88 (s, 1H), 1.84 (m, 1H), 1.40 (s, 1H), 1.23 (s, 9H), 0.96 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 170.7, 136.7, 128.3, 127.6, 123.2, 123.1, 114.9, 82.1, 53.9, 40.9, 34.3, 27.7, 25.1, 24.4, 24.1; mp = 106.2–109.8 °C. HRMS (ESI) m/z: [M + H]+ calcd 304.1907 for C18H25NO3; found 304.1904. [α]D21 = +4.42 (c = 0.5, CHCl3).

Compound 15ae

To a solution of compound 14ae (300 mg, 0.73 mmol) in dry toluene (30 mL, 0.025 M) was added 21a (27 mg, 0.036 mmol) at 21 °C. The reaction was stirred at 50 °C under argon for 7 days. The reaction was quenched with 30 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15ae as a white powdery solid (220 mg, 87% yield, 52% ee). 1H NMR (400 MHz, CDCl3) δ 9.54 (br s, 1H), 7.33 (d, J = 6.8 Hz, 2H), 7.23 (m, 3H), 7.16 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.89 (dd, J = 7.8, 2.7 Hz, 1H), 3.48 (d, J = 13.5 Hz, 1H), 3.30 (d, J = 13.6 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.80 (d, J = 15.6 Hz, 1H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 170.3, 136.8, 136.5, 131.0, 128.2, 127.7, 127.0, 123.2, 122.94, 122.90, 115.3, 82.5, 55.1, 38.4, 34.0, 27.6; mp = 118.8–122.0 °C. HRMS (ESI) m/z: [M + H]+ calcd 338.1751 for C21H23NO3; found 338.1744. [α]D21 = +1.21 (c = 0.5, CHCl3).

Compound 15af

To a solution of compound 14af (120 mg, 0.30 mmol) in dry toluene (12 mL, 0.025 M) was added 21a (11 mg, 0.015 mmol) at 21 °C. The reaction was stirred at 50 °C under argon for 6 days. The reaction was quenched with 12 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15af as a light orange solid (92 mg, 96% yield, 23% ee). 1H NMR (400 MHz, CDCl3) δ 8.40 (br s, 1H), 7.13 (m, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 3.40 (t, J = 6.4 Hz, 2H), 3.31 (s, 3H), 3.20 (d, J = 15.5 Hz, 1H), 2.94 (d, J = 15.4 Hz, 1H), 1.94 (qd, J = 12.6, 4.9 Hz, 2H), 1.79 (dp, J = 17.9, 6.1 Hz, 1H), 1.68 (dp, J = 12.2, 6.0 Hz, 1H), 1.22 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 170.4, 136.7, 128.4, 127.8, 123.3, 122.9, 115.1, 82.3, 72.8, 58.6, 53.5, 34.6, 30.0, 27.7, 25.0; mp = 94.4–95.9 °C. HRMS (ESI) m/z: [M + H]+ calcd 320.1856 for C18H25NO4; found 320.1827. [α]D21 = +2.28 (c = 0.5, CHCl3).

Compound 15ba

To a solution of compound 14ba (200 mg, 0.57 mmol) in dry toluene (23 mL, 0.025 M) was added 21a (22 mg, 0.029 mmol) at 21 °C. The reaction was stirred at 21 °C for 4 days and then 50 °C for 3 days under argon. The reaction was quenched with 24 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15ba as a white solid (150 mg, 94% yield, 40% ee). 1H NMR (400 MHz, CDCl3) δ 7.59 (br s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 3.22 (d, J = 15.5 Hz, 1H), 2.87 (d, J = 15.4 Hz, 1H), 2.23 (s, 3H), 1.49 (s, 3H), 1.19 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 171.2, 135.4, 130.0, 126.0, 122.9, 122.7, 122.4, 82.2, 50.0, 38.0, 27.6, 19.9, 16.8; mp = 101.7–104.0 °C. HRMS (ESI) m/z: [M + H]+ calcd 276.1594 for C16H21NO3; found 276.1513. [α]D24 = +25.66 (c = 0.5, CHCl3).

Compound 15cb

To a solution of compound 14cb (100 mg, 0.27 mmol) in dry toluene (11 mL, 0.025 M) was added 21a (10 mg, 0.014 mmol) at 21 °C. The reaction was stirred at 50 °C under argon for 6 days. The reaction was quenched with 12 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (10% → 100% EtOAc in hexanes) to afford compound 15cb as a yellow powder (53 mg, 66% yield, 56% ee). 1H NMR (400 MHz, CDCl3) δ 7.11 (q, J = 7.2 Hz, 1H), 6.72 (t, J = 8.5 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 3.44 (d, J = 15.6 Hz, 1H), 2.77 (d, J = 15.8 Hz, 1H), 2.04 (m, 1H), 1.94 (m, 1H), 1.27 (s, 9H), 1.04 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 170.0, 160.3 (d, J = 244.9 Hz), 138.6 (d, J = 7.3 Hz), 128.6 (d, J = 9.5 Hz), 110.8 (d, J = 7.4 Hz), 110.5, 110.1 (d, J = 22.0 Hz), 82.3, 53.6, 27.7, 26.5, 26.4, 9.3; 19F NMR (376 MHz, CDCl3) δ −118.9 ppm; mp = 88–90 °C. HRMS (ESI) m/z: [M + H]+ calcd 294.1500 for C16H20FNO3; found 294.1499. [α]D21 = +4.20 (c = 0.5, CHCl3).

Compound 15da

To a solution of compound 14da (99 mg, 0.25 mmol) in dry toluene (10 mL, 0.025 M) was added 21a (9.3 mg, 0.023 mmol) at 21 °C. The reaction was stirred at 21 °C under argon for 5 days. The reaction was quenched with 10 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15da as a white solid (71 mg, 86% yield, 59% ee). 1H NMR (400 MHz, CDCl3) δ 9.29 (br s, 1H), 7.25 (m, 1H), 7.10 (s, 1H), 3.37 (d, J = 15.8 Hz, 1H), 2.93 (d, J = 15.8 Hz, 1H), 1.53 (s, 3H), 1.26 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.8, 170.7, 137.7, 130.4 (q, J = 32.6 Hz), 128.6, 126.6, 125.2, 122.5, 119.9, 112.1, 82.7, 49.9, 37.3, 27.7, 20.0; 19F NMR (376 MHz, (CD3)2CO) δ 62.5 ppm; mp = 113.7–120.1 °C. HRMS (ESI) m/z: [M + H]+ calcd 330.1312 for C16H18F3NO3; found 330.1308. [α]D25 = +22.70 (c = 0.5, CHCl3).

Compound 15ea

To a solution of compound 14ea (120 mg, 0.32 mmol) in dry toluene (13 mL, 0.025 M) was added 21a (12 mg, 0.016 mmol) at 21 °C. The reaction was stirred at 21 °C for 3 days and then 50 °C for 3 days under argon. The reaction was quenched with 14 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15ea as a white solid (74 mg, 78% yield, 59% ee). 1H NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.13 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 3.25 (d, J = 15.8, 1H), 2.83 (d, J = 15.6 Hz, 1H), 1.48 (s, 3H), 1.25 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 170.8, 135.8, 128.09, 128.05, 127.8, 124.4, 116.3, 82.5, 50.0, 37.3, 27.7, 20.0; mp = 159.5–160.9 °C. HRMS (ESI) m/z: [M + H]+ calcd 296.1048 for C15H18ClNO3; found 296.1044. [α]D20 = +4.91 (c = 0.5, CHCl3).

Compound 15eb

To a solution of compound 14eb (130 mg, 0.33 mmol) in dry toluene (13 mL, 0.025 M) was added 21a (13 mg, 0.017 mmol) at 21 °C. The reaction was stirred at 21 °C under argon for 7 days. The reaction was quenched with 14 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (15→ 30% EtOAc in hexanes) to afford compound 15eb as a white solid (86 mg, 83% yield, 58% ee). 1H NMR (400 MHz, CDCl3) δ 9.21 (br s, 1H), 7.10 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 3.17 (d, J = 15.8 Hz, 1H), 2.89 (d, J = 15.7 Hz, 1H), 1.95 (ddt, J = 31.9, 14.1, 6.9 Hz, 2H), 1.26 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 170.1, 135.5, 128.1, 128.0, 127.6, 124.8, 116.4, 82.4, 53.8, 33.6, 27.7, 26.3, 9.3; mp = 158.5–161.8 °C. HRMS (ESI) m/z: [M + H]+ calcd 310.1204 for C16H20ClNO3; found 310.1193. [α]D21 = +3.82 (c = 0.5, CHCl3).

Compound 15fa

To a solution of compound 14fa (100 mg, 0.28 mmol) in dry toluene (11 mL, 0.025 M) was added 21a (10 mg, 0.014 mmol) at 21 °C. The reaction was stirred at 40 °C under argon for 5 days. The reaction was quenched with 12 mL of a 1:1 sodium bicarbonate and water solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude oil residue was purified by flash chromatography on silica gel (20% → 35% EtOAc in hexanes) to afford compound 15fa as a white solid (62 mg, 78% yield, 62% ee). 1H NMR (400 MHz, CDCl3) δ 8.45 (br s, 1H), 6.71 (m, 3H), 3.76 (s, 3H), 3.25 (d, J = 16.0 Hz, 1H), 2.84 (d, J = 15.6 Hz, 1H), 1.48 (s, 3H), 1.26 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 171.2, 155.7, 130.6, 124.1, 116.0, 113.9, 112.9, 82.2, 55.6, 50.0, 37.9, 27.8, 20.0 ppm; mp = 139.2–143.5 °C. HRMS (ESI) m/z: [M + H]+ calcd 292.1543 for C16H21NO4; found 292.1543. [α]D25 = +3.08 (c = 0.5, CHCl3).

Compound 22aa

To a solution of 24aa (24 mg, 0.07 mmol) in dry toluene (3 mL) in a flame-dried round-bottom flask under argon was added (R)-TRIP (2.6 mg, 0.003 mmol). The solution was stirred at 50 °C for 7 days and stirred at 75 °C for an additional 3 days. The solution was then cooled to room temperature and quenched with 5 mL of a 1:1 ratio of sodium bicarbonate and water. The solution was extracted with ethyl acetate (3 × 5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The yellow oil was purified by flash chromatography on silica gel (10% → 50% EtOAc in hexanes) to afford compound 22aa as a thick yellow oil (11 mg, 57% yield, 75% ee). 1H NMR (400 MHz, (CD3)2CO) δ 7.25 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 3.31 (s, 3H), 3.13 (d, J = 15.1 Hz, 1H), 2.86 (d, J = 15.3 Hz, 1H), 1.37 (s, 3H), 1.11 (s, 9H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 171.2, 169.4, 140.9, 127.9, 127.8, 124.4, 122.4, 114.4, 80.9, 50.0, 37.2, 29.4, 26.9, 20.0. HRMS (ESI) m/z: [M + H]+ calcd 276.1594 for C16H21NO3; found 276.1597. [α]D21 = +64.11 (c = 0.5, CHCl3).

Compound 23aa

Upon working up, purifying, and characterizing compound 33aa, compound 23aa was isolated and characterized due to its spontaneous formation in the pursuit to synthesize free amine 33aa. The white powder was purified by flash chromatography on silica gel (20% → 50% EtOAc in hexanes) to afford compound 23aa as a thick white solid (0.20 g, 63% yield). 1H NMR (400 MHz, CDCl3) δ 9.05 (br s, 1H), 7.15 (td, J = 7.7, 1.4 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 6.95 (td, J = 7.6, 1.4 Hz, 1H), 6.82 (dd, J = 8.0, 1.1 Hz, 1H), 4.90 (hept, J = 6.3 Hz, 1H), 3.36 (d, J = 15.6 Hz, 1H), 2.86 (d, J = 15.7 Hz, 1H), 1.50 (s, 3H), 1.09 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.7, 171.5, 137.0, 128.1, 127.9, 123.2, 122.3, 115.4, 69.1, 49.6, 37.3, 21.5, 21.4, 20.0. HRMS (ESI) m/z: [M + H]+ calcd 248.1281 for C14H17NO3; found 248.1276.

Compound 26

To a solution of lithium aluminum hydride (26 mg, 0.69 mmol) in dry THF (0.55 mL) was slowly added a solution of compound 15aa (120 mg, 0.46 mmol, 75% ee) in dry THF (0.35 mL) at 0 °C. The reaction was stirred at −40 °C for 1 h under argon and then stirred at 0 °C for an additional 1 h under argon. At 0 °C, the reaction mixture was diluted with diethyl ether (2 mL), followed by 0.03 mL of water, 0.03 mL of sodium bicarbonate, and 0.09 mL of water. The slurry was stirred at 21 °C for 10 min before 30 mg of MgSO4 was added to the flask. The slurry was passed through a Celite plug, rinsed with ethyl acetate (15 mL), and extracted with ethyl acetate (3 × 10 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (30% → 100% EtOAc in hexanes) to afford compound 26 as a white solid (45 mg, 53% yield, 74% ee). 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 9.43 (br s, 1H), 7.19 (m, 2H), 6.96 (m, 2H), 3.36 (d, J = 16.1 Hz, 1H), 2.78 (d, J = 15.8 Hz, 1H), 1.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 169.7, 137.3, 128.6, 127.7, 122.8, 121.3, 115.1, 52.2, 32.7, 16.5; mp = 132.4–136.0 °C. HRMS (ESI) m/z: [M + H]+ calcd 190.0863 for C11H11NO2; found 190.0857. [α]D23 = −19.51 (c = 0.5, CHCl3).

Compound 27

To a solution of lithium aluminum hydride (44 mg, 1.2 mmol) in dry THF (0.90 mL) was slowly added a solution of compound 15aa (80 mg, 0.31 mmol, 87% ee) in dry THF (0.3 mL) at 0 °C. The reaction was stirred at 0 °C under argon and warmed to 21 °C while running overnight. The reaction mixture was diluted with diethyl ether (3 mL), followed by 0.04 mL of water, 0.04 mL of sodium bicarbonate, and 0.12 mL of water. The slurry was stirred at 21 °C for 15 min before 40 mg of MgSO4 was added to the flask. The slurry was passed through a Celite plug, rinsed with ethyl acetate (15 mL), and extracted with ethyl acetate (3 × 10 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The oil residue was purified by flash chromatography on silica gel (30% → 100% EtOAc in hexanes) to afford compound 27 as a light-yellow oil (25 mg, 46% yield, 85% ee). 1H NMR (400 MHz, CDCl3) δ 6.97 (m, 2H), 6.64 (t, J = 7.4, 1H), 6.52 (d, J = 7.9, 1H), 3.53 (d, J = 10.9 Hz, 1H), 3.42 (d, J = 10.9 Hz, 1H), 3.16 (d, J = 11.3 Hz, 1H), 2.96 (d, J = 11.2 Hz, 1H), 2.83 (br s, 1H), 2.53 (m, 2H), 1.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.4, 130.1, 126.8, 120.4, 117.9, 114.4, 68.9, 48.8, 36.4, 33.4, 22.2. HRMS (ESI) m/z: [M + H]+ calcd 192.1383 for C11H15NO; found 192.1376. [α]D24 = −2.50 (c = 0.5, CHCl3).

Compound 28

To a solution of Na2PdCl4 (13 mg, 0.045 mmol) and sSPhos (55 mg, 0.11 mmol) in water (2.5 mL) was added 15ea (66 mg, 0.22 mmol, 59% ee) in a vial. The solution was stirred at 60 °C for 15 min. A solution of potassium carbonate (120 mg, 0.89 mmol) and 4-tolylboronic acid (61 mg, 0.45 mmol) in a 4:1 mixture of water and acetonitrile (3.5 mL water, 0.85 mL acetonitrile) was then added to the solution containing 15ea. The reaction mixture was then stirred at 80 °C overnight. The solution was diluted with brine (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The white solid was purified by flash chromatography on silica gel (25% → 100% EtOAc in hexanes) to afford compound 28 as an off-white crystalline solid (44 mg, 56% yield, 52% ee). 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 7.42 (t, J = 7.3, 2H), 7.37 (d, J = 10.0 Hz, 2H), 7.23 (m, 2H), 6.85 (dd, J = 9.1, 5.3 Hz, 1H), 3.33 (d, J = 15.6 Hz, 1H), 2.93 (d, J = 15.6 Hz, 1H), 2.38 (s, 3H), 1.52 (s, 3H), 1.24 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.5, 171.2, 137.6, 137.0, 136.3, 136.2, 129.6, 126.7, 126.6, 126.3, 123.1, 115.4, 82.3, 50.2, 37.8, 27.7, 21.2, 20.0; mp = 166.7–169.9 °C. HRMS (ESI) m/z: [M + H]+ calcd 352.1907 for C22H25NO3; found 352.1899. [α]D22 = 12.00 (c = 0.5, CHCl3).

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01060.

  • 1H and 13C spectra of new compounds, HPLC traces of enantioenriched products, detailed guide to compound numbering, DFT details and Cartesian coordinates, X-ray crystallography information (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 14aa–af, 14ba, 14da–fa, 14cb, 14eb, 15aa–af, 15ab, 15da–fa, 15cb, 15eb, 18f, 19a–c, 19e, 20aa, 20da, 20fa, 22aa, 24aa, 26, 27, 28, 32aa, and 33aa (ZIP)

Accession Codes

CCDC 2299046 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Author Information

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  • Corresponding Author
  • Authors
    • Abigail H. Horchar - Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    • Jonathan E. Dean - Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    • Alexander R. Lake - Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    • Jessica E. Carsley - Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    • Tiana R. Lillevig - Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, 301 McIver Street, Greensboro, North Carolina 27412, United States
    • Shubin Liu - Department of Chemistry, The University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, North Carolina 27514, United States;  Orcidhttps://orcid.org/0000-0001-9331-0427
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Financial support is gratefully acknowledged from the National Institutes of Health (R15GM141981, T34GM14949A (T.R.L.), T34GM113860 (J.E.D.), T32AT008938 (A.H.H.)), and the University of North Carolina at Greensboro. Additionally, this material is based in part upon work supported by the National Science Foundation Graduate Research Fellowship Program (J.E.D.) under Grant No. (DGE-1945980). All X-ray crystallography measurements were performed at the UNC Chapel Hill Department of Chemistry X-ray Core Laboratory, and we thank Chun Hsing Chen for his assistance and support by the National Science Foundation under Grant No. (CHE-2117287). We thank Dr. Franklin J. Moy, Dr. Daniel Todd, Dr. Reynaldo Díaz, and Dr. Warren Vidar for assistance with NMR and mass spectrometry data analysis.

References

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This article references 38 other publications.

  1. 1
    Chen, Z.; Sun, J. Enantio- and Diastereoselective Assembly of Tetrahydrofuran and Tetrahydropyran Skeletons with All-Carbon-Substituted Quaternary Stereocenters. Angew. Chem., Int. Ed. 2013, 52 (51), 13593– 13596,  DOI: 10.1002/anie.201306801
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Akiyama, T.; Itoh, J.; Fuchibe, K. Recent Progress in Chiral Brønsted Acid Catalysis. Adv. Synth. Catal. 2006, 348 (9), 999– 1010,  DOI: 10.1002/adsc.200606074
    Google Scholar
    2
    Recent progress in chiral Bronsted acid catalysis
    Akiyama, Takahiko; Itoh, Junji; Fuchibe, Kohei
    Advanced Synthesis & Catalysis (2006), 348 (9), 999-1010CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Hydrogen bond catalysis and Bronsted acid catalysis are rapidly growing areas in organocatalysis. A no. of chiral acid catalysts was developed recently. Recent progress in the chiral Bronsted acid catalysis was reviewed with a focus being placed on thiourea, TADDOL, and phosphoric acids.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvV2ls7g%253D&md5=71b998306fb4d991412cd0ae38f4f332
  3. 3
    Akiyama, T. Stronger Brønsted Acids. Chem. Rev. 2007, 107 (12), 5744– 5758,  DOI: 10.1021/cr068374j
    Google Scholar
    3
    Stronger Bronsted Acids
    Akiyama, Takahiko
    Chemical Reviews (Washington, DC, United States) (2007), 107 (12), 5744-5758CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. The application of Bronsted acids as catalysts in various reactions is discussed in detail.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1GrtL%252FF&md5=2b520bffb085bccc1abc0c38a10699d2
  4. 4
    Kampen, D.; Reisinger, C. M.; List, B. Chiral Brønsted Acids for Asymmetric Organocatalysis. In Asymmetric Organocatalysis; List, B., Ed.; Springer: Berlin, Heidelberg, 2009; pp 1– 37;  DOI: 10.1007/978-3-642-02815-1_1 .
    Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Arcadi, A.; Calcaterra, A.; Fabrizi, G.; Fochetti, A.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; Mazzoccanti, G.; Serraiocco, A. One-Pot Synthesis of Dihydroquinolones by Sequential Reactions of o-Aminobenzyl Alcohol Derivatives with Meldrum’s Acids. Org. Biomol. Chem. 2022, 20 (15), 3160– 3173,  DOI: 10.1039/D2OB00289B
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Bastos Braga, I.; Almir Angnes, R.; Carlos de Lucca Júnior, E.; Carmo Braga, A. A.; Roque Duarte Correia, C. Enantioselective Synthesis of α,β-Unsaturated Aryl Lactams by Heck-Matsuda and Heck-Mizoroki Arylations of Enelactams. Eur. J. Org. Chem. 2022, 2022 (39), e202200377  DOI: 10.1002/ejoc.202200377
    Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54 (10), 3451– 3479,  DOI: 10.1021/jm200187y
    Google Scholar
    7
    The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
    Roughley, Stephen D.; Jordan, Allan M.
    Journal of Medicinal Chemistry (2011), 54 (10), 3451-3479CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. A survey of selected medicinal chem. literature from 2008 was undertaken in order to det. the most common chem. reactions used in the prepn. of drug candidates. In addn. to an examn. of the reactions, the frequency of occurrence of various functional groups in the drug targets was analyzed. The Lipinski parameters and chirality of the surveyed compds. were also discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsrg%253D&md5=a94df26d82bbd58b269ed20aa3253f56
  8. 8
    Heravi, M. M.; Zadsirjan, V. Prescribed Drugs Containing Nitrogen Heterocycles: An Overview. RSC Adv. 2020, 10 (72), 44247– 44311,  DOI: 10.1039/D0RA09198G
    Google Scholar
    8
    Prescribed drugs containing nitrogen heterocycles: an overview
    Heravi, Majid M.; Zadsirjan, Vahideh
    RSC Advances (2020), 10 (72), 44247-44311CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A review. Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biol. active compds. are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs contg. nitrogen heterocycles, describing their pharmacol. properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or contg. N-heterocycles and their synthetic information has been extd. from both scientific journals and the wider patent literature.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1SgsL7N&md5=c24e31ce19fd274ec410ab48b5fcdd5f
  9. 9
    Saldivar-Gonzalez, F. I.; Lenci, E.; Trabocchi, A.; Medina-Franco, J. L. Exploring the Chemical Space and the Bioactivity Profile of Lactams: A Chemoinformatic Study. RSC Adv. 2019, 9 (46), 27105– 27116,  DOI: 10.1039/C9RA04841C
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Jang, J.-H.; Kanoh, K.; Adachi, K.; Shizuri, Y. Awajanomycin, a Cytotoxic γ-Lactone-δ-Lactam Metabolite from Marine-Derived Acremonium Sp. AWA16–1. J. Nat. Prod. 2006, 69 (9), 1358– 1360,  DOI: 10.1021/np060170a
    Google Scholar
    10
    Awajanomycin, a cytotoxic γ-lactone-δ-lactam metabolite from marine-derived Acremonium sp. AWA16-1
    Jang, Jae-Hyuk; Kanoh, Kaneo; Adachi, Kyoko; Shizuri, Yoshikazu
    Journal of Natural Products (2006), 69 (9), 1358-1360CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    The new fungal metabolite awajanomycin (I), which has γ-lactone-δ-lactam rings, was isolated from the marine-derived fungus Acremonium sp. AWA16-1, which had been collected from sea mud off Awajishima Island in Japan. The structure of I was elucidated by spectroscopic anal. and chem. methods. I and its deriv. (II) inhibited the growth of A549 cells with IC50 values of 27.5 and 46.4 μg/mL, resp.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVyltb8%253D&md5=d5d805e3f3b0434ea3246dec544162ce
  11. 11
    A. Ramirez, M. C.; Williams, D. E.; Gubiani, J. R.; Parra, L. L. L.; Santos, M. F. C.; Ferreira, D. D.; Mesquita, J. T.; Tempone, A. G.; Ferreira, A. G.; Padula, V.; Hajdu, E.; Andersen, R. J.; Berlinck, R. G. S. Rearranged Terpenoids from the Marine Sponge Darwinella Cf. Oxeata and Its Predator, the Nudibranch Felimida Grahami. J. Nat. Prod. 2017, 80 (3), 720– 725,  DOI: 10.1021/acs.jnatprod.6b01160
    Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Honda, T.; Namiki, H.; Satoh, F. Palladium-Catalyzed Intramolecular δ-Lactam Formation of Aryl Halides and Amide-Enolates: Syntheses of Cherylline and Latifine. Org. Lett. 2001, 3 (4), 631– 633,  DOI: 10.1021/ol0155337
    Google Scholar
    12
    Palladium-Catalyzed Intramolecular δ-Lactam Formation of Aryl Halides and Amide-Enolates: Syntheses of Cherylline and Latifine
    Honda, Toshio; Namiki, Hidenori; Satoh, Fumie
    Organic Letters (2001), 3 (4), 631-633CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Palladium-catalyzed intramol. carbon-carbon bond formation of aryl halides and amide-enolates gave 4-arylisoquinoline derivs. in good yields, which were further converted into the isoquinoline alkaloids cherylline and latifine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmvVOhug%253D%253D&md5=d1b53a83afea95ba55bd9982970a4e8b
  13. 13
    Aniszewski, T. Chapter 3-Biology of Alkaloids. In Alkaloids, 2nd ed.; Aniszewski, T., Ed.; Elsevier: Boston, 2015; pp 195– 258;  DOI: 10.1016/B978-0-444-59433-4.00003-1 .
    Google Scholar
    There is no corresponding record for this reference.
  14. 14
    Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T. Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of γ-Methylidene-δ-Valerolactones with Isocyanates: Conversion of Racemic Lactones to Enantioenriched Lactams. J. Am. Chem. Soc. 2008, 130 (48), 16174– 16175,  DOI: 10.1021/ja807662b
    Google Scholar
    14
    Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of γ-Methylidene-δ-valerolactones with Isocyanates: Conversion of Racemic Lactones to Enantioenriched Lactams
    Shintani, Ryo; Park, Soyoung; Shirozu, Fumitaka; Murakami, Masataka; Hayashi, Tamio
    Journal of the American Chemical Society (2008), 130 (48), 16174-16175CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A palladium-catalyzed asym. decarboxylative reaction of racemic γ-methylidene-δ-valerolactones with aryl isocyanates has been developed to give enantioenriched 3,3-disubstituted 2-piperidones, i.e. I. High enantioselectivity has been achieved by tuning the ester group on substrate and the substituents of phosphoramidite ligand.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlGrsr3E&md5=6ae68817d475bc94578a4e9fdd4aa92b
  15. 15
    Yamaguchi, Y.; Seino, Y.; Suzuki, A.; Kamei, Y.; Yoshino, T.; Kojima, M.; Matsunaga, S. Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis. Org. Lett. 2022, 24 (12), 2441– 2445,  DOI: 10.1021/acs.orglett.2c00700
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    15
    Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis
    Yamaguchi, Yuto; Seino, Yusuke; Suzuki, Akihiko; Kamei, Yuji; Yoshino, Tatsuhiko; Kojima, Masahiro; Matsunaga, Shigeki
    Organic Letters (2022), 24 (12), 2441-2445CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Intramol. hydroarylation of alkenes through hydrogen atom transfer (HAT) represents a robust method to prep. benzo-fused heterocycles. However, the reported methods have limitations in a variety of accessible cyclic scaffolds. A dual cobalt- and photoredox-catalyzed HAT hydroarylation of alkenes was reported and characterized by higher efficiency in the synthesis of a δ-lactam compared to established protocols. The proposed mechanism was supported by expts. and DFT calcns.
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  16. 16
    Hong, S. Y.; Hwang, Y.; Lee, M.; Chang, S. Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source. Acc. Chem. Res. 2021, 54 (11), 2683– 2700,  DOI: 10.1021/acs.accounts.1c00198
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    16
    Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source
    Hong, Seung Youn; Hwang, Yeongyu; Lee, Minhan; Chang, Sukbok
    Accounts of Chemical Research (2021), 54 (11), 2683-2700CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Catalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chem. since the obtainable nitrogen-contg. motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclin. candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepd. independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, esp. by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addn. to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions. This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- vs. outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temp. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chem. via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decompn., thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chem. space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.
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  17. 17
    Liu, S.; Zhuang, Z.; Qiao, J. X.; Yeung, K.-S.; Su, S.; Cherney, E. C.; Ruan, Z.; Ewing, W. R.; Poss, M. A.; Yu, J.-Q. Ligand Enabled Pd(II)-Catalyzed γ-C(Sp3)-H Lactamization of Native Amides. J. Am. Chem. Soc. 2021, 143 (51), 21657– 21666,  DOI: 10.1021/jacs.1c10183
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    There is no corresponding record for this reference.
  18. 18
    Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. Enantioselective Synthesis of Cyclic Amides and Amines through Mo-Catalyzed Asymmetric Ring-Closing Metathesis. J. Am. Chem. Soc. 2005, 127 (23), 8526– 8533,  DOI: 10.1021/ja051330s
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    18
    Enantioselective Synthesis of Cyclic Amides and Amines through Mo-Catalyzed Asymmetric Ring-Closing Metathesis
    Sattely, Elizabeth S.; Cortez, G. Alexander; Moebius, David C.; Schrock, Richard R.; Hoveyda, Amir H.
    Journal of the American Chemical Society (2005), 127 (23), 8526-8533CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An efficient method for the synthesis of optically enriched N-fused bicyclic structures is reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-, 5,7-, and 5,8-bicyclic amides can be synthesized in ≤ 98% ee. The effects of catalyst structure, olefin substitution, positioning of Lewis basic functional groups and ring size are examd. and discussed in detail. A catalytic asym. method for highly enantioselective (up to 97% ee) synthesis of small- and medium-ring unsatd. cyclic amines is reported; optically enriched products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereoselective functionalizations of olefins within the optically enriched amine products have been carried out. Both catalytic asym. methods include transformations that lead to the formation of trisubstituted as well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high optical purity; such products are not easily accessed by alternative protocols and can be used in enantioselective total syntheses of biol. active mols.
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  19. 19
    Wang, C.; Ge, S. Versatile Cobalt-Catalyzed Enantioselective Entry to Boryl-Functionalized All-Carbon Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2018, 140 (34), 10687– 10690,  DOI: 10.1021/jacs.8b06814
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    19
    Versatile Cobalt-Catalyzed Enantioselective Entry to Boryl-Functionalized All-Carbon Quaternary Stereogenic Centers
    Wang, Chao; Ge, Shaozhong
    Journal of the American Chemical Society (2018), 140 (34), 10687-10690CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    We report an asym. synthesis of chiral boryl-functionalized γ-lactams contg. all-carbon quaternary stereocenters via a Co-catalyzed enantioselective hydroboration/cyclization of amide-tethered 1,6-enynes. These enantio-enriched γ-lactam products can be readily converted to a variety of cyclic and acyclic other chiral γ-lactams, pyrrolidin-2,3-diones, β-amino acid N-carboxyanhydrides, and β-amino carboxylic amides.
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  20. 20
    Dalko, P. I.; Moisan, L. Enantioselective Organocatalysis. Angew. Chem., Int. Ed. 2001, 40 (20), 3726– 3748,  DOI: 10.1002/1521-3773(20011015)40:20<3726::AID-ANIE3726>3.0.CO;2-D
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    There is no corresponding record for this reference.
  21. 21
    Yamai, Y.; Tanaka, A.; Yajima, T.; Ishida, K.; Natsutani, I.; Uesato, S.; Nagaoka, Y.; Sumiyoshi, T. Synthesis of Substituted T-Butyl 3-Methyl-Oxindole-3-Carboxylates from Di-t-Butyl 2-Nitrophenyl-Malonates. Heterocycles 2018, 97 (1), 192– 210,  DOI: 10.3987/COM-17-S(T)2
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    There is no corresponding record for this reference.
  22. 22
    Ishida, K.; Shimizu, M.; Yamai, Y.; Natsutani, I.; Uesato, S.; Nagaoka, Y.; Sumiyoshi, T. Asymmetric Synthesis of T-Butyl 3-Alkyl-Oxindole-3-Carboxylates via Chiral Phosphoric Acid Catalyzed Desymmetrization of Di-t-Butyl 2-Alkyl-2-(2-Aminophenyl)Malonates. Heterocycles 2019, 99 (2), 1398– 1411,  DOI: 10.3987/COM-18-S(F)87
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    There is no corresponding record for this reference.
  23. 23
    Albrecht, Ł.; Richter, B.; Krawczyk, H.; Jørgensen, K. A. Enantioselective Organocatalytic Approach to α-Methylene-δ-Lactones and δ-Lactams. J. Org. Chem. 2008, 73 (21), 8337– 8343,  DOI: 10.1021/jo801582t
    Google Scholar
    23
    Enantioselective Organocatalytic Approach to α-Methylene-δ-lactones and δ-Lactams
    Albrecht, Lukasz; Richter, Bo; Krawczyk, Henryk; Joergensen, Karl Anker
    Journal of Organic Chemistry (2008), 73 (21), 8337-8343CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    We present the first enantioselective organocatalytic approach for the synthesis of α-methylene-δ-lactones and δ-lactams, e.g. I (R = iso-Pr, Et, tert-Bu, X = O, NPh). Our methodol. utilizes the Michael addn. of unmodified aldehydes to Et 2-(diethoxyphosphoryl)acrylate as the key step affording highly enantiomerically enriched adducts, which can be transformed into the target compds. maintaining the high stereoselectivity achieved in the first step. This methodol. has been shown to be general and various optically active γ-substituted α-methylene-δ-lactones and δ-lactams can be easily accessed.
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  24. 24
    Steinhardt, S. E.; Vanderwal, C. D. Complex Polycyclic Lactams from Pericyclic Cascade Reactions of Zincke Aldehydes. J. Am. Chem. Soc. 2009, 131 (22), 7546– 7547,  DOI: 10.1021/ja902439f
    Google Scholar
    24
    Complex Polycyclic Lactams from Pericyclic Cascade Reactions of Zincke Aldehydes
    Steinhardt, Sarah E.; Vanderwal, Christopher D.
    Journal of the American Chemical Society (2009), 131 (22), 7546-7547CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Zincke aldehydes (aminopentadienals) such as I and II (Ts = 4-MeC6H4SO2) undergo stereoselective and chemoselective thermal pericyclic cascade rearrangement and cycloaddn. reactions to yield polycyclic lactams such as III and IV in 30-82% yields. For example, II [prepd. in three steps from 1-tosyl-3-indolecarboxaldehyde, benzylamine, and 1-(2,4-dinitrophenyl)pyridinium chloride] undergoes stereoselective rearrangement and cyclization on microwave irradn. in 1,2-dichlorobenzene at 200° for 4 h to give IV in 30% yield. Cascade rearrangement and cycloaddn. reaction of Zincke aldehydes is proposed to occur by isomerization of the internal alkene of the triene moiety from (E) to (Z), 6π electrocyclic ring closure, [1,5]-sigmatropic shift of hydrogen, 6π electrocyclic ring-opening, and Diels-Alder cycloaddn. The Zincke aldehyde substrates are prepd. by Zincke reactions of allylic and benzylic amines with substituted 1-(2,4-dinitrophenyl)pyridinium salts; unavailable allylic and benzylic amines are prepd. in one or two steps. Thermal Diels-Alder cycloaddn. of a trans-pentadienamide (the olefin diastereomer of the presumed intermediate in one of the cascade reactions) gives a mixt. of diastereomeric products, while the cascade reaction of the corresponding unrearranged Zincke aldehyde gives a single diastereomeric product. The energies of intermediates in the cascade rearrangement and cycloaddn. of a furan-contg. Zincke aldehyde are calcd. to det. whether the furan reacts as an alkene component or as a diene component (with subsequent Cope rearrangement) in the Diels-Alder reaction.
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  25. 25
    McKnight, E. A.; Arora, R.; Pradhan, E.; Fujisato, Y. H.; Ajayi, A. J.; Lautens, M.; Zeng, T.; Le, C. M. BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling. J. Am. Chem. Soc. 2023, 145, 11012,  DOI: 10.1021/jacs.3c03982
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    25
    BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling
    McKnight, E. Ali; Arora, Ramon; Pradhan, Ekadashi; Fujisato, Yuriko H.; Ajayi, Ayonitemi J.; Lautens, Mark; Zeng, Tao; Le, Christine M.
    Journal of the American Chemical Society (2023), 145 (20), 11012-11018CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivs. of known protein kinase inhibitors. Exptl. and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with arom. character. In contrast, this arom. stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.
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  26. 26
    Wilent, J.; Petersen, K. S. Enantioselective Desymmetrization of Diesters. J. Org. Chem. 2014, 79 (5), 2303– 2307,  DOI: 10.1021/jo402853v
    Google Scholar
    26
    Enantioselective Desymmetrization of Diesters
    Wilent, Jennifer; Petersen, Kimberly S.
    Journal of Organic Chemistry (2014), 79 (5), 2303-2307CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Nonracemic oxodihydrofurancarboxylates such as I (R = H, Me, Et, PhCH2) and oxotetrahydropyrancarboxylate II were prepd. in 67-93% yields and in 86-98% ee by desymmetrization of di-tert-Bu hydroxyethylmalonates t-BuO2CCR(CH2CH2OH)CO2t-Bu (R = H, Me, Et, i-Pr, H2C:CHCH2, PhCH2) or a di-tert-Bu hydroxypropylmalonate in the presence of (S)- or (R)-3,3'-bis(2,4,6-triisopropylphenyl)-2,2'-binaphthylphosphoric acids [(S)- or (R)-TRIP]. The di-tert-Bu hydroxyethylmalonates were prepd. in three steps from di-tert-Bu malonate, alkyl halides, and 2-bromoethyl acetate, while the di-tert-Bu hydroxypropylmalonate was prepd. in three steps from di-tert-Bu malonate. I (R = Me) was converted to a nonracemic dihydroxyester and hydroxyamide, a protected quaternary α-amino acid lactone, and a protected α-amino ester.
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  27. 27
    Wilent, J. Enantioselective Synthesis of α,α-Disubstituted Lactones via a Chiral Brønsted Acid Catalyzed Intramolecular Cyclization. Org. Synth. 2016, 93, 75– 87,  DOI: 10.15227/orgsyn.093.0075
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    27
    Enantioselective synthesis of α,α-disubstituted lactones via a chiral bronsted acid catalyzed intramolecular cyclization
    Wilent, Jennifer E.; Qabaja, Ghassan; Petersen, Kimberly S.
    Organic Syntheses (2016), 93 (), 75-87CODEN: ORSYAT; ISSN:0078-6209. (Organic Syntheses, Inc.)
    Authors have developed a highly efficient and generalized procedure for the synthesis of enantioenriched lactones contg. a quaternary center through a Bronsted acid catalyzed desymmetrization of hydroxy diesters. The process has been improved to utilize only 1 mol% of Binol based phosphoric acid and proceed in under 48 h. Thus, reaction of Me malonic acid with Boc2O in t-BuOH in the presence of DMAP gave di-tert-butyl-2-methylmalonate which on alkylation with BrCH2CH2OAc followed by (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate catalyzed intramol. cyclization gave (S)-tert-Bu 3-methyl-2-oxotetrahydrofuran-3-carboxylate.
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  28. 28
    Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114 (18), 9047– 9153,  DOI: 10.1021/cr5001496
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    28
    Complete Field Guide to Asymmetric BINOL-Phosphate Derived Bronsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Bronsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates
    Parmar, Dixit; Sugiono, Erli; Raja, Sadiya; Rueping, Magnus
    Chemical Reviews (Washington, DC, United States) (2014), 114 (18), 9047-9153CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Chiral BINOL-derived Broensted acids have shown themselves to be highly efficient catalysts for a huge plethora of transformations and allow the end user to form C-C, C-H, and a variety of C-X bonds in a highly enantioselective fashion. Although within this category phosphoric acids are strongly known for activating imine substrates, stronger acids in the form of N-triflyl phosphoramides have bridged the gap somewhat to accessing previously thought out-of-reach substrates. Their utility in synthesis however is not solely limited to their acidic character, and more recently they have become extremely powerful chiral counterions for an increasing list of reactions. Furthermore, they can be combined with metal catalysts to create a synergistic effect, which has opened new reaction modes previously not possible with the individual catalysts themselves. Improved understanding of the mechanisms and interactions assocd. between the catalyst and the substrates has allowed research groups to develop highly powerful methodologies. Unfortunately, our understanding is still far from complete, and currently we have a crude understanding of how the catalysts function, but detailed exptl. and computational studies are still required for further progress in the field.
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  29. 29
    Romanov-Michailidis, F.; Romanova-Michaelides, M.; Pupier, M.; Alexakis, A. Enantioselective Halogenative Semi-Pinacol Rearrangement: Extension of Substrate Scope and Mechanistic Investigations. Chem.─Eur. J. 2015, 21 (14), 5561– 5583,  DOI: 10.1002/chem.201406133
    Google Scholar
    There is no corresponding record for this reference.
  30. 30
    Hiramatsu, K.; Honjo, T.; Rauniyar, V.; Toste, F. D. Enantioselective Synthesis of Fluoro-Dihydroquinazolones and -Benzooxazinones by Fluorination-Initiated Asymmetric Cyclization Reactions. ACS Catal. 2016, 6 (1), 151– 154,  DOI: 10.1021/acscatal.5b02182
    Google Scholar
    There is no corresponding record for this reference.
  31. 31
    Phipps, R. J.; Hiramatsu, K.; Toste, F. D. Asymmetric Fluorination of Enamides: Access to α-Fluoroimines Using an Anionic Chiral Phase-Transfer Catalyst. J. Am. Chem. Soc. 2012, 134 (20), 8376– 8379,  DOI: 10.1021/ja303959p
    Google Scholar
    31
    Asymmetric Fluorination of Enamides: Access to α-Fluoroimines Using an Anionic Chiral Phase-Transfer Catalyst
    Phipps, Robert J.; Hiramatsu, Kenichi; Toste, F. Dean
    Journal of the American Chemical Society (2012), 134 (20), 8376-8379CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The use of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst in a nonpolar solvent allows the enantioselective fluorination of enamides using Selectfluor as the fluorinating reagent. We demonstrate that a wide range of stable and synthetically versatile α-(fluoro)benzoylimines can be readily accessed with high enantioselectivity. These compds. have the potential to be readily elaborated into a range of highly stereodefined β-fluoroamines, compds. that constitute highly valuable building blocks of particular importance in the synthesis of pharmaceuticals.
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  32. 32
    Changotra, A.; Sunoj, R. B. Origin of Kinetic Resolution of Hydroxy Esters through Catalytic Enantioselective Lactonization by Chiral Phosphoric Acids. Org. Lett. 2016, 18 (15), 3730– 3733,  DOI: 10.1021/acs.orglett.6b01752
    Google Scholar
    There is no corresponding record for this reference.
  33. 33
    Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2019; https://gaussian.com/citation/.
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    There is no corresponding record for this reference.
  34. 34
    Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120 (1), 215– 241,  DOI: 10.1007/s00214-007-0310-x
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    34
    The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
    Zhao, Yan; Truhlar, Donald G.
    Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
    We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
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  35. 35
    McLean, A. D.; Chandler, G. S. Contracted Gaussian Basis Sets for Molecular Calculations. I. Second Row Atoms, Z = 11–18. J. Chem. Phys. 1980, 72 (10), 5639– 5648,  DOI: 10.1063/1.438980
    Google Scholar
    35
    Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z = 11-18
    McLean, A. D.; Chandler, G. S.
    Journal of Chemical Physics (1980), 72 (10), 5639-48CODEN: JCPSA6; ISSN:0021-9606.
    Contracted Gaussian basis sets for mol. calcns. are derived from uncontracted (12,8) and (12,9) sets for the neutral second row atoms, Z = 11-18, and for the neg. ions P-, S-, and Cl-. Calcns. on Na...2p63p, 2P and Mg...2p63s3p, 3P are used to derive contracted Gaussian functions to describe the 3p orbital in these atoms, necessary in mol. applications. The derived basis sets range from minimal, through double-zeta, to the largest set which has a triple-zeta basis for the 3p orbital, double-zeta for the remaining. Where necessary to avoid unacceptable energy losses in at. wave functions expanded in the contracted Gaussians, a given uncontracted Gaussian function is used in two contracted functions. These tabulations provide a hierarchy of basis sets to be used in designing a convergent sequence of mol. computations, and to establish the reliability of the mol. properties under study.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXksFCnu7c%253D&md5=c273cc5d7ac2eef1d9c13825d81c68ac
  36. 36
    Chipman, D. M. Reaction Field Treatment of Charge Penetration. J. Chem. Phys. 2000, 112 (13), 5558– 5565,  DOI: 10.1063/1.481133
    Google Scholar
    36
    Reaction field treatment of charge penetration
    Chipman, Daniel M.
    Journal of Chemical Physics (2000), 112 (13), 5558-5565CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Treatment of the important electrostatic effects of solvation by means of reaction field theory is becoming common in electronic structure calcns. on mols. Most extant reaction field methods neglect or crudely approx. the often important influence of vol. polarization arising from solute charge that quantum mech. penetrates outside the cavity that nominally encloses it. This work proposes and examines a new formulation that provides an accurate simulation of vol. polarization effects while being much simpler to implement and use than an exact treatment. Detailed comparisons with other related methods are also given.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhsl2is7s%253D&md5=e422d1ee6143a561829747f3d64ba22a
  37. 37
    Sharma, S. V.; Pubill-Ulldemolins, C.; Marelli, E.; Goss, R. J. M. An Expedient, Mild and Aqueous Method for Suzuki-Miyaura Diversification of (Hetero)Aryl Halides or (Poly)Chlorinated Pharmaceuticals. Org. Chem. Front. 2021, 8 (20), 5722– 5727,  DOI: 10.1039/D1QO00919B
    Google Scholar
    There is no corresponding record for this reference.
  38. 38
    PubChem. 2-(Bromomethyl)-1-methoxy-4-nitrobenzene; https://pubchem.ncbi.nlm.nih.gov/compound/77516 (accessed 2024–04–30).
    Google Scholar
    There is no corresponding record for this reference.

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  • Abstract

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    Figure 1

    Figure 1. Significance of the chiral lactams produced in this work is highlighted by the featured lactam-containing compounds.

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    Scheme 1

    Scheme 1. Literature Precedence, Other Lactamization Strategies, and Reaction Scheme for the Current Studya
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    aTRIP = 3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate.

    Scheme 2

    Scheme 2. Synthetic Route to the Precursor Amines
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    Figure 2

    Figure 2. Chiral phosphoric acid catalysts tested in the optimization process.

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    Figure 3

    Figure 3. (a) DFT and skeleton models of the transition state leading to the S enantiomer between 21a and 14aa, showing the concerted formation of the C–N lactam bond and the tetrahedral intermediate. (b) DFT model showing the bidentate binding of the transition state leading to the S enantiomer versus the monodentate binding of the transition state leading to the R enantiomer

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    Figure 4

    Figure 4. Scope of lactam substrates produced. Consult the Supporting Information for more detail.

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    Scheme 3

    Scheme 3. Large-Scale Cyclization Using Decreased Catalyst Loading
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    Scheme 4

    Scheme 4. Substrates Can Be Further Manipulated To Increase Complexity and Adjust Chemical Properties
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  • References

    This article references 38 other publications.

    1. 1
      Chen, Z.; Sun, J. Enantio- and Diastereoselective Assembly of Tetrahydrofuran and Tetrahydropyran Skeletons with All-Carbon-Substituted Quaternary Stereocenters. Angew. Chem., Int. Ed. 2013, 52 (51), 13593– 13596,  DOI: 10.1002/anie.201306801
      There is no corresponding record for this reference.
    2. 2
      Akiyama, T.; Itoh, J.; Fuchibe, K. Recent Progress in Chiral Brønsted Acid Catalysis. Adv. Synth. Catal. 2006, 348 (9), 999– 1010,  DOI: 10.1002/adsc.200606074
      2
      Recent progress in chiral Bronsted acid catalysis
      Akiyama, Takahiko; Itoh, Junji; Fuchibe, Kohei
      Advanced Synthesis & Catalysis (2006), 348 (9), 999-1010CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Hydrogen bond catalysis and Bronsted acid catalysis are rapidly growing areas in organocatalysis. A no. of chiral acid catalysts was developed recently. Recent progress in the chiral Bronsted acid catalysis was reviewed with a focus being placed on thiourea, TADDOL, and phosphoric acids.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvV2ls7g%253D&md5=71b998306fb4d991412cd0ae38f4f332
    3. 3
      Akiyama, T. Stronger Brønsted Acids. Chem. Rev. 2007, 107 (12), 5744– 5758,  DOI: 10.1021/cr068374j
      3
      Stronger Bronsted Acids
      Akiyama, Takahiko
      Chemical Reviews (Washington, DC, United States) (2007), 107 (12), 5744-5758CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. The application of Bronsted acids as catalysts in various reactions is discussed in detail.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1GrtL%252FF&md5=2b520bffb085bccc1abc0c38a10699d2
    4. 4
      Kampen, D.; Reisinger, C. M.; List, B. Chiral Brønsted Acids for Asymmetric Organocatalysis. In Asymmetric Organocatalysis; List, B., Ed.; Springer: Berlin, Heidelberg, 2009; pp 1– 37;  DOI: 10.1007/978-3-642-02815-1_1 .
      There is no corresponding record for this reference.
    5. 5
      Arcadi, A.; Calcaterra, A.; Fabrizi, G.; Fochetti, A.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; Mazzoccanti, G.; Serraiocco, A. One-Pot Synthesis of Dihydroquinolones by Sequential Reactions of o-Aminobenzyl Alcohol Derivatives with Meldrum’s Acids. Org. Biomol. Chem. 2022, 20 (15), 3160– 3173,  DOI: 10.1039/D2OB00289B
      There is no corresponding record for this reference.
    6. 6
      Bastos Braga, I.; Almir Angnes, R.; Carlos de Lucca Júnior, E.; Carmo Braga, A. A.; Roque Duarte Correia, C. Enantioselective Synthesis of α,β-Unsaturated Aryl Lactams by Heck-Matsuda and Heck-Mizoroki Arylations of Enelactams. Eur. J. Org. Chem. 2022, 2022 (39), e202200377  DOI: 10.1002/ejoc.202200377
      There is no corresponding record for this reference.
    7. 7
      Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54 (10), 3451– 3479,  DOI: 10.1021/jm200187y
      7
      The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
      Roughley, Stephen D.; Jordan, Allan M.
      Journal of Medicinal Chemistry (2011), 54 (10), 3451-3479CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. A survey of selected medicinal chem. literature from 2008 was undertaken in order to det. the most common chem. reactions used in the prepn. of drug candidates. In addn. to an examn. of the reactions, the frequency of occurrence of various functional groups in the drug targets was analyzed. The Lipinski parameters and chirality of the surveyed compds. were also discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsrg%253D&md5=a94df26d82bbd58b269ed20aa3253f56
    8. 8
      Heravi, M. M.; Zadsirjan, V. Prescribed Drugs Containing Nitrogen Heterocycles: An Overview. RSC Adv. 2020, 10 (72), 44247– 44311,  DOI: 10.1039/D0RA09198G
      8
      Prescribed drugs containing nitrogen heterocycles: an overview
      Heravi, Majid M.; Zadsirjan, Vahideh
      RSC Advances (2020), 10 (72), 44247-44311CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A review. Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biol. active compds. are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs contg. nitrogen heterocycles, describing their pharmacol. properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or contg. N-heterocycles and their synthetic information has been extd. from both scientific journals and the wider patent literature.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1SgsL7N&md5=c24e31ce19fd274ec410ab48b5fcdd5f
    9. 9
      Saldivar-Gonzalez, F. I.; Lenci, E.; Trabocchi, A.; Medina-Franco, J. L. Exploring the Chemical Space and the Bioactivity Profile of Lactams: A Chemoinformatic Study. RSC Adv. 2019, 9 (46), 27105– 27116,  DOI: 10.1039/C9RA04841C
      There is no corresponding record for this reference.
    10. 10
      Jang, J.-H.; Kanoh, K.; Adachi, K.; Shizuri, Y. Awajanomycin, a Cytotoxic γ-Lactone-δ-Lactam Metabolite from Marine-Derived Acremonium Sp. AWA16–1. J. Nat. Prod. 2006, 69 (9), 1358– 1360,  DOI: 10.1021/np060170a
      10
      Awajanomycin, a cytotoxic γ-lactone-δ-lactam metabolite from marine-derived Acremonium sp. AWA16-1
      Jang, Jae-Hyuk; Kanoh, Kaneo; Adachi, Kyoko; Shizuri, Yoshikazu
      Journal of Natural Products (2006), 69 (9), 1358-1360CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      The new fungal metabolite awajanomycin (I), which has γ-lactone-δ-lactam rings, was isolated from the marine-derived fungus Acremonium sp. AWA16-1, which had been collected from sea mud off Awajishima Island in Japan. The structure of I was elucidated by spectroscopic anal. and chem. methods. I and its deriv. (II) inhibited the growth of A549 cells with IC50 values of 27.5 and 46.4 μg/mL, resp.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVyltb8%253D&md5=d5d805e3f3b0434ea3246dec544162ce
    11. 11
      A. Ramirez, M. C.; Williams, D. E.; Gubiani, J. R.; Parra, L. L. L.; Santos, M. F. C.; Ferreira, D. D.; Mesquita, J. T.; Tempone, A. G.; Ferreira, A. G.; Padula, V.; Hajdu, E.; Andersen, R. J.; Berlinck, R. G. S. Rearranged Terpenoids from the Marine Sponge Darwinella Cf. Oxeata and Its Predator, the Nudibranch Felimida Grahami. J. Nat. Prod. 2017, 80 (3), 720– 725,  DOI: 10.1021/acs.jnatprod.6b01160
      There is no corresponding record for this reference.
    12. 12
      Honda, T.; Namiki, H.; Satoh, F. Palladium-Catalyzed Intramolecular δ-Lactam Formation of Aryl Halides and Amide-Enolates: Syntheses of Cherylline and Latifine. Org. Lett. 2001, 3 (4), 631– 633,  DOI: 10.1021/ol0155337
      12
      Palladium-Catalyzed Intramolecular δ-Lactam Formation of Aryl Halides and Amide-Enolates: Syntheses of Cherylline and Latifine
      Honda, Toshio; Namiki, Hidenori; Satoh, Fumie
      Organic Letters (2001), 3 (4), 631-633CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Palladium-catalyzed intramol. carbon-carbon bond formation of aryl halides and amide-enolates gave 4-arylisoquinoline derivs. in good yields, which were further converted into the isoquinoline alkaloids cherylline and latifine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmvVOhug%253D%253D&md5=d1b53a83afea95ba55bd9982970a4e8b
    13. 13
      Aniszewski, T. Chapter 3-Biology of Alkaloids. In Alkaloids, 2nd ed.; Aniszewski, T., Ed.; Elsevier: Boston, 2015; pp 195– 258;  DOI: 10.1016/B978-0-444-59433-4.00003-1 .
      There is no corresponding record for this reference.
    14. 14
      Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T. Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of γ-Methylidene-δ-Valerolactones with Isocyanates: Conversion of Racemic Lactones to Enantioenriched Lactams. J. Am. Chem. Soc. 2008, 130 (48), 16174– 16175,  DOI: 10.1021/ja807662b
      14
      Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of γ-Methylidene-δ-valerolactones with Isocyanates: Conversion of Racemic Lactones to Enantioenriched Lactams
      Shintani, Ryo; Park, Soyoung; Shirozu, Fumitaka; Murakami, Masataka; Hayashi, Tamio
      Journal of the American Chemical Society (2008), 130 (48), 16174-16175CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A palladium-catalyzed asym. decarboxylative reaction of racemic γ-methylidene-δ-valerolactones with aryl isocyanates has been developed to give enantioenriched 3,3-disubstituted 2-piperidones, i.e. I. High enantioselectivity has been achieved by tuning the ester group on substrate and the substituents of phosphoramidite ligand.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlGrsr3E&md5=6ae68817d475bc94578a4e9fdd4aa92b
    15. 15
      Yamaguchi, Y.; Seino, Y.; Suzuki, A.; Kamei, Y.; Yoshino, T.; Kojima, M.; Matsunaga, S. Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis. Org. Lett. 2022, 24 (12), 2441– 2445,  DOI: 10.1021/acs.orglett.2c00700
      15
      Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis
      Yamaguchi, Yuto; Seino, Yusuke; Suzuki, Akihiko; Kamei, Yuji; Yoshino, Tatsuhiko; Kojima, Masahiro; Matsunaga, Shigeki
      Organic Letters (2022), 24 (12), 2441-2445CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Intramol. hydroarylation of alkenes through hydrogen atom transfer (HAT) represents a robust method to prep. benzo-fused heterocycles. However, the reported methods have limitations in a variety of accessible cyclic scaffolds. A dual cobalt- and photoredox-catalyzed HAT hydroarylation of alkenes was reported and characterized by higher efficiency in the synthesis of a δ-lactam compared to established protocols. The proposed mechanism was supported by expts. and DFT calcns.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XnsFKhur8%253D&md5=7cad45959f7ba4c3878fc6fa3aa4cba9
    16. 16
      Hong, S. Y.; Hwang, Y.; Lee, M.; Chang, S. Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source. Acc. Chem. Res. 2021, 54 (11), 2683– 2700,  DOI: 10.1021/acs.accounts.1c00198
      16
      Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source
      Hong, Seung Youn; Hwang, Yeongyu; Lee, Minhan; Chang, Sukbok
      Accounts of Chemical Research (2021), 54 (11), 2683-2700CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Catalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chem. since the obtainable nitrogen-contg. motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclin. candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepd. independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, esp. by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addn. to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions. This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- vs. outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temp. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chem. via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decompn., thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chem. space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.
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    17. 17
      Liu, S.; Zhuang, Z.; Qiao, J. X.; Yeung, K.-S.; Su, S.; Cherney, E. C.; Ruan, Z.; Ewing, W. R.; Poss, M. A.; Yu, J.-Q. Ligand Enabled Pd(II)-Catalyzed γ-C(Sp3)-H Lactamization of Native Amides. J. Am. Chem. Soc. 2021, 143 (51), 21657– 21666,  DOI: 10.1021/jacs.1c10183
      There is no corresponding record for this reference.
    18. 18
      Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. Enantioselective Synthesis of Cyclic Amides and Amines through Mo-Catalyzed Asymmetric Ring-Closing Metathesis. J. Am. Chem. Soc. 2005, 127 (23), 8526– 8533,  DOI: 10.1021/ja051330s
      18
      Enantioselective Synthesis of Cyclic Amides and Amines through Mo-Catalyzed Asymmetric Ring-Closing Metathesis
      Sattely, Elizabeth S.; Cortez, G. Alexander; Moebius, David C.; Schrock, Richard R.; Hoveyda, Amir H.
      Journal of the American Chemical Society (2005), 127 (23), 8526-8533CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An efficient method for the synthesis of optically enriched N-fused bicyclic structures is reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-, 5,7-, and 5,8-bicyclic amides can be synthesized in ≤ 98% ee. The effects of catalyst structure, olefin substitution, positioning of Lewis basic functional groups and ring size are examd. and discussed in detail. A catalytic asym. method for highly enantioselective (up to 97% ee) synthesis of small- and medium-ring unsatd. cyclic amines is reported; optically enriched products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereoselective functionalizations of olefins within the optically enriched amine products have been carried out. Both catalytic asym. methods include transformations that lead to the formation of trisubstituted as well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high optical purity; such products are not easily accessed by alternative protocols and can be used in enantioselective total syntheses of biol. active mols.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktlKjtLg%253D&md5=0ff3405ba41a6b8d8b617edab1948ad9
    19. 19
      Wang, C.; Ge, S. Versatile Cobalt-Catalyzed Enantioselective Entry to Boryl-Functionalized All-Carbon Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2018, 140 (34), 10687– 10690,  DOI: 10.1021/jacs.8b06814
      19
      Versatile Cobalt-Catalyzed Enantioselective Entry to Boryl-Functionalized All-Carbon Quaternary Stereogenic Centers
      Wang, Chao; Ge, Shaozhong
      Journal of the American Chemical Society (2018), 140 (34), 10687-10690CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      We report an asym. synthesis of chiral boryl-functionalized γ-lactams contg. all-carbon quaternary stereocenters via a Co-catalyzed enantioselective hydroboration/cyclization of amide-tethered 1,6-enynes. These enantio-enriched γ-lactam products can be readily converted to a variety of cyclic and acyclic other chiral γ-lactams, pyrrolidin-2,3-diones, β-amino acid N-carboxyanhydrides, and β-amino carboxylic amides.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFerurjM&md5=032dca668a5b8df2f88282b2e6f968be
    20. 20
      Dalko, P. I.; Moisan, L. Enantioselective Organocatalysis. Angew. Chem., Int. Ed. 2001, 40 (20), 3726– 3748,  DOI: 10.1002/1521-3773(20011015)40:20<3726::AID-ANIE3726>3.0.CO;2-D
      There is no corresponding record for this reference.
    21. 21
      Yamai, Y.; Tanaka, A.; Yajima, T.; Ishida, K.; Natsutani, I.; Uesato, S.; Nagaoka, Y.; Sumiyoshi, T. Synthesis of Substituted T-Butyl 3-Methyl-Oxindole-3-Carboxylates from Di-t-Butyl 2-Nitrophenyl-Malonates. Heterocycles 2018, 97 (1), 192– 210,  DOI: 10.3987/COM-17-S(T)2
      There is no corresponding record for this reference.
    22. 22
      Ishida, K.; Shimizu, M.; Yamai, Y.; Natsutani, I.; Uesato, S.; Nagaoka, Y.; Sumiyoshi, T. Asymmetric Synthesis of T-Butyl 3-Alkyl-Oxindole-3-Carboxylates via Chiral Phosphoric Acid Catalyzed Desymmetrization of Di-t-Butyl 2-Alkyl-2-(2-Aminophenyl)Malonates. Heterocycles 2019, 99 (2), 1398– 1411,  DOI: 10.3987/COM-18-S(F)87
      There is no corresponding record for this reference.
    23. 23
      Albrecht, Ł.; Richter, B.; Krawczyk, H.; Jørgensen, K. A. Enantioselective Organocatalytic Approach to α-Methylene-δ-Lactones and δ-Lactams. J. Org. Chem. 2008, 73 (21), 8337– 8343,  DOI: 10.1021/jo801582t
      23
      Enantioselective Organocatalytic Approach to α-Methylene-δ-lactones and δ-Lactams
      Albrecht, Lukasz; Richter, Bo; Krawczyk, Henryk; Joergensen, Karl Anker
      Journal of Organic Chemistry (2008), 73 (21), 8337-8343CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      We present the first enantioselective organocatalytic approach for the synthesis of α-methylene-δ-lactones and δ-lactams, e.g. I (R = iso-Pr, Et, tert-Bu, X = O, NPh). Our methodol. utilizes the Michael addn. of unmodified aldehydes to Et 2-(diethoxyphosphoryl)acrylate as the key step affording highly enantiomerically enriched adducts, which can be transformed into the target compds. maintaining the high stereoselectivity achieved in the first step. This methodol. has been shown to be general and various optically active γ-substituted α-methylene-δ-lactones and δ-lactams can be easily accessed.
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    24. 24
      Steinhardt, S. E.; Vanderwal, C. D. Complex Polycyclic Lactams from Pericyclic Cascade Reactions of Zincke Aldehydes. J. Am. Chem. Soc. 2009, 131 (22), 7546– 7547,  DOI: 10.1021/ja902439f
      24
      Complex Polycyclic Lactams from Pericyclic Cascade Reactions of Zincke Aldehydes
      Steinhardt, Sarah E.; Vanderwal, Christopher D.
      Journal of the American Chemical Society (2009), 131 (22), 7546-7547CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Zincke aldehydes (aminopentadienals) such as I and II (Ts = 4-MeC6H4SO2) undergo stereoselective and chemoselective thermal pericyclic cascade rearrangement and cycloaddn. reactions to yield polycyclic lactams such as III and IV in 30-82% yields. For example, II [prepd. in three steps from 1-tosyl-3-indolecarboxaldehyde, benzylamine, and 1-(2,4-dinitrophenyl)pyridinium chloride] undergoes stereoselective rearrangement and cyclization on microwave irradn. in 1,2-dichlorobenzene at 200° for 4 h to give IV in 30% yield. Cascade rearrangement and cycloaddn. reaction of Zincke aldehydes is proposed to occur by isomerization of the internal alkene of the triene moiety from (E) to (Z), 6π electrocyclic ring closure, [1,5]-sigmatropic shift of hydrogen, 6π electrocyclic ring-opening, and Diels-Alder cycloaddn. The Zincke aldehyde substrates are prepd. by Zincke reactions of allylic and benzylic amines with substituted 1-(2,4-dinitrophenyl)pyridinium salts; unavailable allylic and benzylic amines are prepd. in one or two steps. Thermal Diels-Alder cycloaddn. of a trans-pentadienamide (the olefin diastereomer of the presumed intermediate in one of the cascade reactions) gives a mixt. of diastereomeric products, while the cascade reaction of the corresponding unrearranged Zincke aldehyde gives a single diastereomeric product. The energies of intermediates in the cascade rearrangement and cycloaddn. of a furan-contg. Zincke aldehyde are calcd. to det. whether the furan reacts as an alkene component or as a diene component (with subsequent Cope rearrangement) in the Diels-Alder reaction.
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    25. 25
      McKnight, E. A.; Arora, R.; Pradhan, E.; Fujisato, Y. H.; Ajayi, A. J.; Lautens, M.; Zeng, T.; Le, C. M. BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling. J. Am. Chem. Soc. 2023, 145, 11012,  DOI: 10.1021/jacs.3c03982
      25
      BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling
      McKnight, E. Ali; Arora, Ramon; Pradhan, Ekadashi; Fujisato, Yuriko H.; Ajayi, Ayonitemi J.; Lautens, Mark; Zeng, Tao; Le, Christine M.
      Journal of the American Chemical Society (2023), 145 (20), 11012-11018CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivs. of known protein kinase inhibitors. Exptl. and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with arom. character. In contrast, this arom. stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.
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    26. 26
      Wilent, J.; Petersen, K. S. Enantioselective Desymmetrization of Diesters. J. Org. Chem. 2014, 79 (5), 2303– 2307,  DOI: 10.1021/jo402853v
      26
      Enantioselective Desymmetrization of Diesters
      Wilent, Jennifer; Petersen, Kimberly S.
      Journal of Organic Chemistry (2014), 79 (5), 2303-2307CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Nonracemic oxodihydrofurancarboxylates such as I (R = H, Me, Et, PhCH2) and oxotetrahydropyrancarboxylate II were prepd. in 67-93% yields and in 86-98% ee by desymmetrization of di-tert-Bu hydroxyethylmalonates t-BuO2CCR(CH2CH2OH)CO2t-Bu (R = H, Me, Et, i-Pr, H2C:CHCH2, PhCH2) or a di-tert-Bu hydroxypropylmalonate in the presence of (S)- or (R)-3,3'-bis(2,4,6-triisopropylphenyl)-2,2'-binaphthylphosphoric acids [(S)- or (R)-TRIP]. The di-tert-Bu hydroxyethylmalonates were prepd. in three steps from di-tert-Bu malonate, alkyl halides, and 2-bromoethyl acetate, while the di-tert-Bu hydroxypropylmalonate was prepd. in three steps from di-tert-Bu malonate. I (R = Me) was converted to a nonracemic dihydroxyester and hydroxyamide, a protected quaternary α-amino acid lactone, and a protected α-amino ester.
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    27. 27
      Wilent, J. Enantioselective Synthesis of α,α-Disubstituted Lactones via a Chiral Brønsted Acid Catalyzed Intramolecular Cyclization. Org. Synth. 2016, 93, 75– 87,  DOI: 10.15227/orgsyn.093.0075
      27
      Enantioselective synthesis of α,α-disubstituted lactones via a chiral bronsted acid catalyzed intramolecular cyclization
      Wilent, Jennifer E.; Qabaja, Ghassan; Petersen, Kimberly S.
      Organic Syntheses (2016), 93 (), 75-87CODEN: ORSYAT; ISSN:0078-6209. (Organic Syntheses, Inc.)
      Authors have developed a highly efficient and generalized procedure for the synthesis of enantioenriched lactones contg. a quaternary center through a Bronsted acid catalyzed desymmetrization of hydroxy diesters. The process has been improved to utilize only 1 mol% of Binol based phosphoric acid and proceed in under 48 h. Thus, reaction of Me malonic acid with Boc2O in t-BuOH in the presence of DMAP gave di-tert-butyl-2-methylmalonate which on alkylation with BrCH2CH2OAc followed by (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate catalyzed intramol. cyclization gave (S)-tert-Bu 3-methyl-2-oxotetrahydrofuran-3-carboxylate.
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    28. 28
      Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114 (18), 9047– 9153,  DOI: 10.1021/cr5001496
      28
      Complete Field Guide to Asymmetric BINOL-Phosphate Derived Bronsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Bronsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates
      Parmar, Dixit; Sugiono, Erli; Raja, Sadiya; Rueping, Magnus
      Chemical Reviews (Washington, DC, United States) (2014), 114 (18), 9047-9153CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Chiral BINOL-derived Broensted acids have shown themselves to be highly efficient catalysts for a huge plethora of transformations and allow the end user to form C-C, C-H, and a variety of C-X bonds in a highly enantioselective fashion. Although within this category phosphoric acids are strongly known for activating imine substrates, stronger acids in the form of N-triflyl phosphoramides have bridged the gap somewhat to accessing previously thought out-of-reach substrates. Their utility in synthesis however is not solely limited to their acidic character, and more recently they have become extremely powerful chiral counterions for an increasing list of reactions. Furthermore, they can be combined with metal catalysts to create a synergistic effect, which has opened new reaction modes previously not possible with the individual catalysts themselves. Improved understanding of the mechanisms and interactions assocd. between the catalyst and the substrates has allowed research groups to develop highly powerful methodologies. Unfortunately, our understanding is still far from complete, and currently we have a crude understanding of how the catalysts function, but detailed exptl. and computational studies are still required for further progress in the field.
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    29. 29
      Romanov-Michailidis, F.; Romanova-Michaelides, M.; Pupier, M.; Alexakis, A. Enantioselective Halogenative Semi-Pinacol Rearrangement: Extension of Substrate Scope and Mechanistic Investigations. Chem.─Eur. J. 2015, 21 (14), 5561– 5583,  DOI: 10.1002/chem.201406133
      There is no corresponding record for this reference.
    30. 30
      Hiramatsu, K.; Honjo, T.; Rauniyar, V.; Toste, F. D. Enantioselective Synthesis of Fluoro-Dihydroquinazolones and -Benzooxazinones by Fluorination-Initiated Asymmetric Cyclization Reactions. ACS Catal. 2016, 6 (1), 151– 154,  DOI: 10.1021/acscatal.5b02182
      There is no corresponding record for this reference.
    31. 31
      Phipps, R. J.; Hiramatsu, K.; Toste, F. D. Asymmetric Fluorination of Enamides: Access to α-Fluoroimines Using an Anionic Chiral Phase-Transfer Catalyst. J. Am. Chem. Soc. 2012, 134 (20), 8376– 8379,  DOI: 10.1021/ja303959p
      31
      Asymmetric Fluorination of Enamides: Access to α-Fluoroimines Using an Anionic Chiral Phase-Transfer Catalyst
      Phipps, Robert J.; Hiramatsu, Kenichi; Toste, F. Dean
      Journal of the American Chemical Society (2012), 134 (20), 8376-8379CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The use of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst in a nonpolar solvent allows the enantioselective fluorination of enamides using Selectfluor as the fluorinating reagent. We demonstrate that a wide range of stable and synthetically versatile α-(fluoro)benzoylimines can be readily accessed with high enantioselectivity. These compds. have the potential to be readily elaborated into a range of highly stereodefined β-fluoroamines, compds. that constitute highly valuable building blocks of particular importance in the synthesis of pharmaceuticals.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvV2gu7k%253D&md5=6b9d1d5d6ccfe0916cef487ed9bfcb6c
    32. 32
      Changotra, A.; Sunoj, R. B. Origin of Kinetic Resolution of Hydroxy Esters through Catalytic Enantioselective Lactonization by Chiral Phosphoric Acids. Org. Lett. 2016, 18 (15), 3730– 3733,  DOI: 10.1021/acs.orglett.6b01752
      There is no corresponding record for this reference.
    33. 33
      Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2019; https://gaussian.com/citation/.
      There is no corresponding record for this reference.
    34. 34
      Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120 (1), 215– 241,  DOI: 10.1007/s00214-007-0310-x
      34
      The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
      Zhao, Yan; Truhlar, Donald G.
      Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
      We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
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    35. 35
      McLean, A. D.; Chandler, G. S. Contracted Gaussian Basis Sets for Molecular Calculations. I. Second Row Atoms, Z = 11–18. J. Chem. Phys. 1980, 72 (10), 5639– 5648,  DOI: 10.1063/1.438980
      35
      Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z = 11-18
      McLean, A. D.; Chandler, G. S.
      Journal of Chemical Physics (1980), 72 (10), 5639-48CODEN: JCPSA6; ISSN:0021-9606.
      Contracted Gaussian basis sets for mol. calcns. are derived from uncontracted (12,8) and (12,9) sets for the neutral second row atoms, Z = 11-18, and for the neg. ions P-, S-, and Cl-. Calcns. on Na...2p63p, 2P and Mg...2p63s3p, 3P are used to derive contracted Gaussian functions to describe the 3p orbital in these atoms, necessary in mol. applications. The derived basis sets range from minimal, through double-zeta, to the largest set which has a triple-zeta basis for the 3p orbital, double-zeta for the remaining. Where necessary to avoid unacceptable energy losses in at. wave functions expanded in the contracted Gaussians, a given uncontracted Gaussian function is used in two contracted functions. These tabulations provide a hierarchy of basis sets to be used in designing a convergent sequence of mol. computations, and to establish the reliability of the mol. properties under study.
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    36. 36
      Chipman, D. M. Reaction Field Treatment of Charge Penetration. J. Chem. Phys. 2000, 112 (13), 5558– 5565,  DOI: 10.1063/1.481133
      36
      Reaction field treatment of charge penetration
      Chipman, Daniel M.
      Journal of Chemical Physics (2000), 112 (13), 5558-5565CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      Treatment of the important electrostatic effects of solvation by means of reaction field theory is becoming common in electronic structure calcns. on mols. Most extant reaction field methods neglect or crudely approx. the often important influence of vol. polarization arising from solute charge that quantum mech. penetrates outside the cavity that nominally encloses it. This work proposes and examines a new formulation that provides an accurate simulation of vol. polarization effects while being much simpler to implement and use than an exact treatment. Detailed comparisons with other related methods are also given.
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    37. 37
      Sharma, S. V.; Pubill-Ulldemolins, C.; Marelli, E.; Goss, R. J. M. An Expedient, Mild and Aqueous Method for Suzuki-Miyaura Diversification of (Hetero)Aryl Halides or (Poly)Chlorinated Pharmaceuticals. Org. Chem. Front. 2021, 8 (20), 5722– 5727,  DOI: 10.1039/D1QO00919B
      There is no corresponding record for this reference.
    38. 38
      PubChem. 2-(Bromomethyl)-1-methoxy-4-nitrobenzene; https://pubchem.ncbi.nlm.nih.gov/compound/77516 (accessed 2024–04–30).
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01060.

    • 1H and 13C spectra of new compounds, HPLC traces of enantioenriched products, detailed guide to compound numbering, DFT details and Cartesian coordinates, X-ray crystallography information (PDF)

    • FAIR data, including the primary NMR FID files, for compounds 14aa–af, 14ba, 14da–fa, 14cb, 14eb, 15aa–af, 15ab, 15da–fa, 15cb, 15eb, 18f, 19a–c, 19e, 20aa, 20da, 20fa, 22aa, 24aa, 26, 27, 28, 32aa, and 33aa (ZIP)

    Accession Codes

    CCDC 2299046 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.


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