The effect of four- and six-membered ring-size analogs (azetidine- and piperidine-2-carboxylic acid, H-Aze-OH and H-Pip-OH) of proline on the stability of the collagen triple helix was examined. Computational and nuclear magnetic resonance spectroscopic studies with model compounds and thermal denaturation experiments with collagen peptides showed that the ring-size analogs destabilize the triple helix to a similar extent by either mismatching backbone dihedral angles ϕ and ψ (Pip) or by an unfavorable trans/cis amide bond ratio (Aze).

The macrocyclization of resorcinol and odd-numbered bisdioxolanes under acidic conditions produced feet-to-feet connected trisresorcinarenes possessing three resorcinarene units linked with odd-numbered alkyl chains. The formation of trisresorcinarenes was confirmed using high-resolution mass spectrometry and NMR spectroscopy. The trisresorcinarenes were isolated as protected forms in moderate yields. The protected trisresorcinarenes exhibited D_3h symmetry in conformation in solution. Crystal structure analysis revealed that the protected trisresorcinarenes possess large inner spaces surrounded by three resorcinarene units.

A CuSO₄-catalyzed tandem benzylic C–H insertion cyclization of toluene derivatives and isonitriles is described. The naturally abundant salt CuSO₄ serves as a low-cost ligand-free redox catalyst. This reaction provides a practical modular synthesis of N-aryl indoles from isonitriles.

A novel synthesis of 3-nitrosoindoles starting from easily available N-nitrosoanilines and sulfoxonium ylides via Rh(III)-catalyzed acylmethylation and trifluoroacetic acid (TFA)-mediated nitroso transfer/cyclization cascade reaction in one pot has been developed. The N-nitroso group plays a dual role as a versatile directing group and internal nitrosation reagent. Rh(III)-catalyzed C–H activation/C–C bond formation and TFA-mediated N–N bond cleavage/formation of two C–N bonds are involved in this reaction. This process is scalable and avoids external oxidation. DMSO and H₂O are produced as byproducts. Moreover, further chemical transformations of the desired products enhance its synthetic value.

We report the first Borono–Strecker reaction, a multicomponent reaction for the synthesis of α-aminoboronic acid derivatives from readily available carbonyl compounds, amines, and B₂pin₂. Diverse α-aminoboronates, including aryl-substituted and tertiary examples, were synthesized in moderate to high isolated yields. Compounds were prepared bearing N-(2-pyridyl) groups, which form five-membered rings via N–B coordination, as well as systems bearing noncoordinating N-aryl groups, the latter being isolated and fully characterized for the first time.

A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.

The first catalytic enantioselective hydrocyanation of allenes catalyzed by a (R,R)-Ph-BPE–Ni(0) complex catalyst has been accomplished. Numerous optically active allylic nitriles were obtained in good yield with excellent enantioselectivities (up to 98% ee).

A synthesis of the carbopyronine dye Carboxy ATTO 647N from simple materials is reported. This route proceeds in 11 forward steps from 3-bromoaniline with the key xanthone intermediate formed using a new oxidation methodology. The step utilizes an oxidation cycle with base, water, iodine, and more than doubles the yield of the standard permanganate oxidation methodology, accessing gram-scale quantities of this late-stage product. From this, Carboxy ATTO 647N was prepared in only four additional steps. This facile route to a complex fluorophore is expected to enable further studies in fluorescence imaging.

An efficient oxidative NHC-catalyzed one-step transformation of (S)- or (R)-8-oxocitronellal to nepetalactone (NL) in enantio- and diastereomerically pure form has been developed. Several new and “easy to make” N-Mes- or N-Dipp-substituted 1,2,4-triazolium salts carrying nitroaromatic groups on N1 were synthesized and evaluated as precatalysts in combination with base and stoichiometric organic oxidant. Under optimized conditions, NLs are accessible in very good yields and diastereomerically pure under mild conditions. The oxidant used could be recovered and recycled under operationally simple conditions.

A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido[1,2-a]benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies indicated that the formed pyrimido[1,2-a]benzimidazole exhibited moderate cytotoxic activity against tumor cells.

A highly enantioselective formal [4 + 2] annulation involving electron-deficient allenes as C2-synthons has been developed under bifunctional phosphonium salt catalysis. With this catalytic protocol, a wide range of synthetically interesting and highly functionalized chiral 4H-pyran derivatives were readily prepared in good yields (up to 99%) with outstanding diastereo- and enantioselectivities (up to >20:1 dr, up to >99.9% ee). The utility and the practicality of this method were demonstrated by the gram-scale reaction and facile elaboration. Of note, this is the first example of an asymmetric annulation reaction involving allenic reactants under a phase-transfer catalysis system.

An asymmetric addition of substituted 1,3-pentadienylboronates to aldehydes via Brønsted acid catalysis is reported. Under the developed conditions, a variety of synthetically useful 1,4-pentadien-3-yl carbinols were obtained in good yields with high enantioselectivities in the presence of a catalytic amount of a chiral phosphoric acid.

Herpotrichones A and B (1 and 2), two intermolecular [4 + 2] adducts with an unprecedented pentacyclic 6/6/6/6/3 skeleton, were isolated from Herpotrichia sp. SF09, an isopod-associated fungus, along with a new shunt product protrichone (3). Their structures were elucidated by the analysis of spectroscopic data, residual dipolar coupling (RDC)-based computer-assisted 3D structure elucidation (CASE-3D), and single-crystal X-ray diffraction in combination with electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were assessed to be potent anti-neuroinflammatory agents in lipopolysaccharide (LPS)-induced BV-2 microglial cells with the half maximal inhibitory concentration (IC₅₀) values of 0.41 and 0.11 μM, respectively.

Continuous flow has been used widely in process chemistry and academic settings for various applications. However, initial reaction discovery has generally remained “batch-exclusive” despite the existence of efficient, reproducible flow systems. We hereby disclose a workflow to bridge the gap between early medicinal chemistry efforts and process-scale development, showcased by the discovery and optimization of a metallaphotoredox-catalyzed cross-coupling between benzylic chlorides and aryl bromides, followed by two library syntheses of complex drug-like compounds.

A palladium-catalyzed oxidative cascade carbonylative carbocyclization of enallenols was developed. Under mild reaction conditions, a range of cis-fused [5,5] bicyclic γ-lactones and γ-lactams with a 1,3-diene motif were obtained in good yields with high diastereoselectivity. The obtained lactone/lactam products are viable substrates for a stereoselective Diels–Alder reaction with N-phenylmaleimide, providing polycyclic compounds with increased molecular complexity.

We report the oxyalkynylation of thiiranes and thietanes using ethynylbenziodoxolone reagents (EBXs) to readily access functionalized building blocks bearing an alkynyl, a benzoate, and an iodide group. The reaction proceeds with high atom efficiency most likely through an alkynyl–episulfonium intermediate. The transformation is copper-catalyzed and compatible with a large array of thiiranes and thietanes.

A catalyst-controlled highly chemoselective and regioselective intramolecular cycloamidation of triazol-1-ylbenzamides toward the synthesis of scarcely known heterocycles is reported. In the presence of a palladium catalyst, this cycloisomerization reaction afforded substituted benzotriazlolodiazepin-7-ones via intramolecular insertion of a palladium into C–C triple bond in a 7-exo-dig way. Alternatively, the use of a silver catalyst in the reaction produced substituted benzotriazolodiazocin-8-ones in a highly regioselective manner through 8-endo-dig intramolecular ring closure.

The first (3 + 2)/(3 + 2) sequential annulation of γ-vinyl allenoates with alkylidenemalononitriles enabled by phosphine catalysis has been reported. A broad range of structurally dense tetra- and penta-substituted bicyclic[3,3,0]octene derivatives, containing a quaternary center and three sequential stereogenic center, were synthesized in good to excellent yields. In this approach, three new C–C bonds are formed in one pot, and εC and αC of γ-vinyl allenoate are two electrophilic centers, whereas its γC exhibits nucleophilic reactivity.

Rh(III)-catalyzed coupling between acrylic acids and yndienones has been realized for the synthesis of cis-hydrobenzofuranone. The reaction proceeded in excellent regio- and stereoselectivity under mild and redox-neutral conditions via a sequence of carboxylic acid-directed olefinic C–H activation, alkyne insertion, and Michael addition. Representative products were found to exhibit cytotoxicity toward the A549 cancer cell line at micromolar levels.

An unprecedented carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent was developed, thus providing the β-trifluoromethyl-α-substituted ketones with a broad scope and moderate to high chemical yields. Notably, this process includes a single-electron-transfer process and utilizes the persistent N-heterocyclic-carbene-bound radical as a key intermediate to trigger the cascade radical cross-coupling.

An exclusive thiophene-fused polycyclic π-conjugated 2-arylbenzo[4,5]thieno[2,3-d]thiazole skeleton was constructed via a one-pot CuCl-mediated three-component reaction, using 2-(2-bromophenyl)acetonitrile and aromatic aldehydes as substrates and elemental sulfur as sulfur source in the presence of K₂CO₃ and 1,10-phen in DMSO. A plausible reaction mechanism was proposed, which involved formation of benzo[b]thiophen-2-amines through cyclization of 2-bromophenyl acetonitrile and sulfur, and subsequent intramolecular condensation/dehydrogenation with aromatic aldehydes.

DFT study suggests that the C–H cleavage involved in the C(sp³)–H amination catalyzed by manganese perchlorophthalocyanine complex [Mn^III(ClPc)]⁺ proceeds via hydride transfer (HYT), instead of hydrogen atom transfer (HAT), thus elucidating why the reaction favors aminating the electron-rich C–H bond, rather than that with smaller bond dissociation energy preferred by HAT. Detailed analyses indicate the HYT actually occurs via concerted electron and hydrogen atom transfers and the redox-active ClPc ligand enables the HYT.

The first Pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids is achieved, providing versatile 2-aryldihydropyridinones for facile synthesis of highly functionalized 2-arylpiperidines. Key to this arylation is the use of non-phosphine-ligand palladium precatalyst. The substrate scope is demonstrated with >26 examples, and the utility of 2-aryldihydropyridinones is illustrated by the synthesis of a small collection of 2-arylpiperidines with substituents or functional groups at any carbon (C2–C6) as well as two NK₁ receptor antagonists (+)-CP-999,94 and (+)-L-733,060.

A synthesis of β-ketosulfones via sulfination of aryl methyl ketones and aryl acetylenes with sodium sulfinates under mild electrochemical conditions, in moderate to good chemical yields, is described. In particular, an electrochemical sulfination reaction of alkynes with sulfinate salts has never been explored. An environmentally friendly characteristic of this reaction is that it uses electricity as a valuable energy source for electrochemical synthesis of β-ketosulfones. This strategy is more convenient and practical compared to previous approaches.

Herein, we describe a method for the catalytic enantioselective α-amination of α-substituted acyclic 1,3-ketoamides and 1,3-amidoesters that affords the products possessing N-substituted quaternary stereocenters with a chiral N-heterocyclic carbene (NHC). The reaction is based on the utilization of an intrinsic Brønsted base characteristic of NHC that enables the catalytic formation of a chiral ion pair comprising the enolate and the azolium ion. A series of challenging open-chain α-substituted 1,3-dicarbonyls are aminated via this method with ee’s of ≤99%.

Two distinctive transition-metal-promoted aerobic oxidation protocols have been developed for the synthesis of isoquinolones from 2-vinylbenzaldehydes and aniline derivatives. Thus, the one-pot tandem reaction sequence of imine formation, thermal 6π-electrocyclization, followed by either Cu(OAc)₂-mediated or Pd(OAc)₂-catalyzed aerobic oxidation protocol allowed the ready access to isoquinolone derivatives. The control experiments revealed that the 1,2-dihydroisoquinoline intermediates from the 6π-electrocyclization of 1-azatrienes were aerobically oxidized to isoquinolones in the presence of either Cu(OAc)₂ or Pd(OAc)₂ catalyst.

Aryl radicals generated in the aqueous phase of biphasic mixtures have—regardless of a comparably low polarity— a strong preference to react with aromatic substrates in the aqueous phase and not to undergo phase-transfer into a lipophilic phase, independent from the presence of a surfactant. These results represent an important prerequisite toward future studies in biological systems, which typically consist of various compartments of either hydrophilic or lipophilic character.

Here we report an organocatalytic double Ugi reaction combining the enantioselective process and ee enhancement in a single operation to afford the chiral Ugi products with very high ee values. Both bisisocyanides and bisanilines tethered by carbonate and diester, respectively, were designed to accomplish this double multicomponent reaction that formed 10 new chemical bonds (4 C–N, 2 C–C, 2 C–O, and 2 N–H bonds). The strategy was further applied for the fast construction of an enantiomerically enriched macrocycle.

We herein report a phosphine-mediated domino process of MBH-type reaction/umpolung γ-addition through the rational integration of the privileged reactivities of alkynoate. Simply by manipulating the nucleophilic reagent, the developed protocol offers a facile, diversity-oriented construction of a wide range of three-substituted coumarins.

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.

Substituted α-alkylidene cyclopentenones are formed in up to 93% yield by the intramolecular capture of vinyl cations with pendent alkenes. An increased level of substitution at the β-position of the β-hydroxy-α-diazoketone starting material changed the course of the reaction to instead give a lactone product. A reaction path that involves bond reorganization via an acylium ion intermediate is proposed to explain these results. Substrate scope studies showed that more stable vinyl cations gave higher α-alkylidene cyclopentenone yields. This study provides a mild and efficient method to form α-alkylidene cyclopentenones that complements C–H insertion and Nazarov cyclization strategies.

We report a novel and practical one-pot Rh(III)-catalyzed strategy to construct benzimidazo[1,2-a]quinolines from readily available imidamides and anthranils. The cascade reaction proceeds via a C–H amination–cyclization–cyclization process in ionic liquid without any additives and possesses simple operation, moderate-to-high yield, and broad substrate scope features, which will provide the reference for the construction of biologically active fused benzimidazoles.

Various functionalized tribenzo[b,d,f]azepines were prepared efficiently with the readily available 2-aminobenzoic acids and cyclic hypervalent diaryliodonium reagents as starting materials under Pd(II) catalysis. The key of this step-economical protocol is that the carboxylic acid functionality was employed as both a traceless directing group for the N–H activation/arylation and a functional handle for the tandem π-extended decarboxylative annulation.

We report on the spontaneous, reversible intramolecular transesterification of natural labdane lactones. Through extensive spectroscopic analysis, the interconversion between the two tautomers was investigated, which could be retarded when the free hydroxy group was acetylated or the exocyclic double bond of the lactone ring was mutated. Besides, a conversion mechanism was postulated, and the energy barriers were calculated by density functional theory calculations. Furthermore, the tautomers were found to inhibit the virulence of the efflux pump-deficient Candida albicans DSY654.

Described herein is the development of a new synthetic route to cyclic amidines from quinolines. The borane-catalyzed 1,4-hydrosilylation of quinoline was utilized for the dearomatization of the quinolines. The dearomatized enamine intermediate was subsequently reacted with a broad range of organic azides to produce the corresponding cyclic amidines (3,4-dihydroquinolinimines) via a [3 + 2] cycloaddition pathway. Preliminary mechanistic studies suggested that the hydride shift was involved during the cycloaddition.

Total synthesis of caesalpinnone A was achieved in 12 steps starting from resorcinol. Key features of the synthesis include BINOL-phosphoric acid catalyzed [4 + 2] cycloaddition, trans-selective nucleophilic substitution, deallylation/oxa-Michael addition cascade, and late-stage photo-Fries rearrangement.

We describe the synthesis of the unusual bicyclic sugar bradyrhizose in 14 steps and a 6% overall yield from d-glucose. The synthesis involves the elaboration of a trans-fused carbocyclic ring onto the preexisting glucopyranose framework followed by adjustment of the oxidation levels. Key steps include radical extension of the glucopyranose side chain, ring closing metathesis, allylic oxidation, Luche reduction, hydroxy-directed epoxidation, and acid-catalyzed epoxide opening at the more substituted position.

A visible-light-driven regioselective dearomative cyclization between 2-benzyl-2-bromomalonate and alkynes under mild conditions leading to the formation of spiro[4,5]decanes has been developed. In the presence of H₂O, a variety of 2-benzyl-2-bromomalonates smoothly undergo 5-exo-dig radical dearomative cyclization with alkynes to afford the corresponding spiro[4,5]decanes in moderate to good yield in a step-economical manner under oxidant-free conditions.

DNA-binding polyamides are synthetic oligomers of pyrrole/imidazole units with high specificity and affinity for double-stranded DNA. To increase their synthetic diversity, we report a mild methodology based on 4-methyltrityl (Mtt) solid phase peptide synthesis (SPPS), whose building blocks are more accessible than the standard Fmoc and Boc SPPS ones. We demonstrate the robustness of the approach by preparing and studying a hairpin with all precursors. Importantly, our strategy is orthogonal and compatible with sensitive molecules and could be readily automated.

Herein we report an efficient total synthesis of lipid-anchor-appended core trisaccharides of lipoteichoic acids of Streptococcus pneumoniae and Streptococcus oralis Uo5. The key features include the expedient synthesis of the rare sugar 2,4,6-trideoxy-2-acetamido-4-amino-d-Galp building block via one-pot sequential S_N2 reactions and the α-selective coupling of d-thioglucoside with the diacyl glycerol acceptor to construct a common disaccharide acceptor, which was utilized in the total synthesis of target molecules 1 and 2.

An efficient palladium-catalyzed approach to access various functionalized (Z)-3-benzylidene-isoindoline-1-ones and (Z)-3-benzylidene(imino)isobenzofuranones via a denitrogenative tandem alkynylation/cyclization reaction of 1,2,3-benzotriazin-4(3H)-ones with aromatic terminal alkynes is described. Furthermore, a denitrogenative ortho-alkynylation reaction of 1,2,3-benzotriazinones with aliphatic terminal alkynes is also developed. The reaction proceeds through a five-membered azapalladacyclic intermediate with the extrusion of a nitrogen molecule. The significance of the reaction is also demonstrated by a one-pot synthesis of (Z)-3-benzylideneisobenzofuran-1(3H)-one derivatives in good to high yields.

To achieve a complete closed-shell quinoidal state, bis(dicyanomethylene)-substituted quinoidal terthiophenes bearing benzene annelation at all thiophene rings were synthesized using a retro-Diels–Alder reaction as the key step. The unique structures and properties originating from the full benzene annelation were revealed by X-ray analysis as well as property measurements. Organic solar cells based on the combination of a donor polymer with a quinoidal terthiophene as an acceptor showed a power conversion efficiency of 1.39%.

An efficient strategy for the synthesis of the potent phospholipase A₂ inhibitors spongidine A and D is presented. The tetracyclic core of the natural products was assembled via an intramolecular hydrogen atom transfer initiated Minisci reaction. A divergent late-stage functionalization of the tetracyclic ring system was also used to achieve a concise synthesis of petrosaspongiolide L methyl ester.

Late-stage derivatization of pharmaceutically relevant scaffolds relies on the availability of highly functional-group tolerant reactions. Reactions that increase the sp³ character of molecules enable the pursuit of more selective and well-tolerated pharmaceuticals. Herein, we report the use of sp³–sp² cross-electrophile reductive couplings to modify a generic ATP-competitive kinase inhibitor with a broad range of primary and secondary alkyl halide coupling partners.

We developed a chemoselective oxidative dearomative spiroetherification and spiroamination of arenols using I⁺/oxone catalysis. The intramolecular dearomative C–O and C–N couplings proceeded much more efficiently under slightly acidic conditions to give the corresponding spiro adducts in higher yields compared with previous methods using transition metal or hypervalent iodine catalysts. Control experiments suggested that both hypoiodous acid and iodine might be active species for these reactions.

Concise syntheses of the Hancock alkaloids (−)-angustureine and (−)-cuspareine are presented, applying and refining a recently developed rhodium-catalyzed hydroamination for the stereoselective construction of the chiral secondary amine. Furthermore, the syntheses include an allene synthesis via boron–magnesium exchange as well as the construction of the tetrahydroquinoline motive via a hydroboration/Suzuki–Miyaura coupling sequence.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

The photosensitized p-anisaldehyde-mediated addition of sulfonylcyanides onto the π-system of cyclobutenes is shown to afford highly functionalized cyclobutanes in high yields and diastereocontrol. The homochiral cyclobutene precursors are accessible on multigram scale in two steps through an asymmetric [2 + 2] cycloaddition/vinyl thioether reduction sequence. The enantiopure cyclobutylnitriles can be elaborated further through SmI₂-mediated ring opening or converted into new enantiopure cyclobutenes through base-mediated sulfone elimination.

Eight unprecedent diterpenoids, botryotins A–H (1–8), were obtained from Botryotinia fuckeliana. They represent three novel carbon skeletons with 6/6/5/5 (1), 6/6/5/6 (2–6), and 6/6/6/5 (7 and 8) tetracyclic scaffolds. Their structures were determined by detailed spectroscopic analysis and chemical derivatization as well as quantum chemical calculation of the ECD and OR data. Botryotin A (1) exhibited a moderate antiallergic effect (IC₅₀ = 0.2 mM). A plausible biosynthetic pathway for 1–8 was proposed.

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a′ with the best PDE4 inhibitory activity (IC₅₀ = 0.18 μM).

A simple chiral binuclear titanium complex ((S)-Ti₂L₃Na₄) was first prepared and served as an excellent chiral sensor for discriminating a variety of chiral ammoniums by ¹H NMR. In the presence of trifluoroacetic acid, the in-situ-generated ammoniums of varied amines can be effectively resolved by (S)-Ti₂L₃Na₄. The different binding forces between (S)-Ti₂L₃Na₄ and two enantiomers of analytes generate different shielding effects on two enantiomers, resulting in a split in the distinguishable chemical shift.

A vast range of novel TADDOL-based diphosphite ligands were first synthesized and applied in the nickel-catalyzed asymmetric hydrocyanation of disubstituted methylenecyclopropanes. By employing these new catalysts, the conversion of diverse methylenecyclopropanes into their corresponding allylic nitriles was first enabled, in good yield with excellent enantioselectivities.

Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)–hydride complex to the olefins proceeded regioselectively, and the nucleophilic addition of benzotriazoles occurred selectively at their N²-positions. The synthetic utility of the obtained N²-alkylated benzotriazoles as stable amine protecting groups under various reaction conditions was demonstrated, and the products were also transformed into primary amines by zinc-mediated reduction.

Manipulating the equilibrium between a ketone and an enol by light opens up ample opportunities in material chemistry and photopharmacology. By incorporating β-ketoester into the ethene bridge of a photoactive diarylethene, we achieved reversible light-induced tautomerization to give thermally stable enol. In a pristine state, the tautomeric equilibrium is almost completely shifted toward the ketone. Photocyclization of diarylethene results in a new equilibrium containing a significant fraction of the enol tautomer.

Benzothiazoles are synthesized from thiobenzanilides using riboflavin as a photosensitizer and potassium peroxydisulfate as a sacrificial oxidizing agent under visible light irradiation. The methodology accepts a broad range of functional groups and affords the 2-substituted benzothiazoles by transition-metal-free organic photoredox catalysis under very mild conditions.

A divergent strategy for precise construction of SCF₂H or SeCF₂H groups on heteroarenes generated in situ from CF₃-containing 1,3-enynes was developed. Reactions of readily available 1,3-enynes with S₈ and ClCF₂H provided 3-SCF₂H-4-CF₃-thiophenes via a cascade thiophene construction/selective C3 position thiolation/difluoromethylthiolation process, as did a series of 3-SeCF₂H-4-CF₃-selenophenes by similar strategies. The plausible radical annulation process for the construction of the thiophene ring and difluorocarbene generated in situ was confirmed by experiment.

A Cu-catalyzed synthesis of a range of value-added 1,1-diarylalkanes by radical alkylarylation of vinylarenes with alkyl peroxides as masked alkyl electrophiles is reported. The reaction features broad substrate scope, good functional group tolerance, and mild reaction conditions. Various bioactive molecules and key pharmaceutical intermediates have been easily synthesized by this method, demonstrating its synthetic value.

An efficient silver catalyzed annulation reaction of aryne with nitriles to generate quinazolines is described. Arynes generated from triynes or tetraynes through a hexadehydro Diels–Alder reaction readily participated in an [A + 2B] mode of annulation with nitriles in the presence of AgSbF₆ catalyst. The mechanism was explored by DFT calculations, which supports the silver-catalyzed formation of nitrilium ion as a key intermediate. This annulation generates an array of polysubstituted novel quinazoline derivatives with excellent regioselectivity.

A methodology for the synthesis of 7,12-dihydro-5H-6,12-methanodibenzo[c,f]azocines from aromatic aldehydes and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine using catalysis by trifluoroacetic and perchloric acids is described. The developed protocol was applied for the synthesis of N-unsubstituted and N-methyl-4-aryltetrahydroisoquinolines.

In this work, an interesting and practical procedure for the synthesis of 1,2-diketones from aryl halides and organoaluminum reagents has been developed. Employing tert-butyl isocyanide as the CO source and palladium as the catalyst, the desired 1,2-diketones were isolated in good to excellent yields with good functional group tolerance. Concerning the reaction partners, besides aryl halides, both alkyl- and arylaluminum reagents were all suitable substrates here.

Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are described. Crucial to these reactions is the formation of a silver–aryne complex, which shows differential reactivity toward isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of an aryne–isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the nitrilium of an aryne–nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the structure of the nitrile employed.

A novel Brønsted acid-catalyzed reaction of alkynyl thioethers with o-hydroxybenzyl alcohols via an unexpected formal [4 + 2] annulation has been developed. This metal-free protocol leads to the facile and practical synthesis of valuable polysubstituted 2H-chromenes in mostly good to excellent yields under mild reaction conditions and features a wide substrate scope and excellent functional group tolerance.

The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of the fatty acid chain are created by utilizing Merck-Carreira and Marshall’s propargylation reaction, Evans’ alkylation methodology, and Noyori’s transfer hydrogenation protocol.

An enantioselective chromium/cobalt-cocatalyzed three-component reaction involving a carbohalide, an alkyne, and an aldehyde was developed, leading to valuable highly functionalized allylic alcohols. A modified Kishi’s tridentate sulfonamide ligand was used as the coupling catalyst. A broad array of substrates were well-tolerated under the mild reaction conditions. The versatile strategy offers a straightforward method to introduce fluorine-containing functionalities into allylic alcohols.

A Rh(III)-catalyzed annulative coupling of 3,5-diarylisothiazoles and alkynes is reported. The N–S bond in the isothiazole ring acts as an internal oxidant to regenerate the Rh(III) species in combination with an external Cu(II) oxidant, and the corresponding 1:2 coupling products are obtained. The remarkable difference in the reaction outcome between isothiazoles and the relevant isoxazoles has been investigated by DFT calculations, revealing that the relative stability of the enolate intermediates dictates the product selectivity.

A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised catalyst and with an acenapthoquinone-derived boron ligand. Because of the broad functional group tolerance of this reaction, it can be a versatile tool for organic synthesis. Applications to the construction of (R)-coniine and (−)-indolizidine 209D are described.

Although hydrosulfonylation of alkynes is an ideal process to generate β-keto sulfones, such an approach is rarely implemented. Here we reported a facile and efficient graphitic carbon nitride (p-g-C₃N₄) photocatalyzed hydrosulfonylation of alkynes with the insertion of sulfur dioxide in aerobic conditions. Controlled experiments and ESR results indicated both the superoxide radicals and valence band holes played an important role in the reaction. Further isotope experiments confirmed the oxygen atom of the products comes from H₂O, while the O₂ plays an important role in the reaction by quenching the DABCO radical cation. The metal-free heterogeneous semiconductor is fully recyclable at least 6 times without significant reducing activity. Furthermore, this reaction could be carried out under solar light irradiation and was applicable for a large-scale reaction with conserved results.

A concise synthesis of yaequinolones J1 and J2 is reported. The route is based on the aryne insertion into the σ-C–N bond of an unsymmetric imide followed by a diastereoselective aldol cyclization of the resulting N-acylated aminobenzophenone. The chromene motif is generated in the first step by an organocatalytic tandem Knoevenagel electrocyclization of citral and 2-bromoresorcinol. The approach adheres to the ideality principle, using almost exclusively strategic bond-forming reactions.

Piperazine-containing compounds serve as one of the most important classes of compounds throughout all fields of chemistry. Alas, current synthetic methods have fallen short of providing a general method for the synthesis of highly decorated piperazine fragments. Herein, we present a site-selective approach to the C–H functionalization of existing piperazine compounds using photoredox catalysis. This manifold relies on the predictable differentiation of electronically distinct nitrogen centers within the piperazine framework, granting access to novel C-alkylated variants of the starting piperazines.

Iron-catalyzed hydrogen atom transfer-mediated intermolecular C–C coupling reactions between alkenes and tosylhydrazones, followed by in situ cleavage of the tosylhydrazine intermediates using Et₃N, are described. The process involves a new strategic bond disconnection resulting in the reductive alkylation of nonactivated alkenes. The reaction is operationally simple, proceeds under mild conditions, and has a wide substrate scope.

A novel strategy for the synthesis of 3-hydroxycarbazoles involving the consecutive propargylation/palladium-catalyzed hydroxylative benzannulation of indole-2-carbonyls with propargylic alcohols has been exploited. This one-pot procedure leads to a wide range of substituted 3-hydroxycarbazoles in high yield with a broad substrate scope. The method was further extended to access furano-carbazole derivatives from dialkynols via tandem annulations.

A general intermolecular reductive Heck reaction of organohalides with both terminal and internal unactivated aliphatic alkenes has been first realized in high yield with complete anti-Markovnikov selectivity. The challenging vinyl bromides, aryl chlorides, and polysubstituted internal alkenes were first applied. More than 100 remote carbofunctionalized alkyl carboxylic acid derivatives were rapidly synthesized from easily accessible starting materials. The synthesis of drug molecules has further demonstrated the wide synthetic utility of this scalable strategy. Preliminary mechanistic studies are consistent with the proposed catalytic cycle.

Electrophilic C–H borylation of arenes using boron triiodide has been developed. This reaction proceeded smoothly in the absence of additives, and the diiodoboryl group was installed at the most sterically accessible carbon, where the HOMO is localized to a certain extent. Moreover, regioselective multiple borylation of polycyclic aromatic compounds was achieved by using excess boron triiodide. The borylated intermediates were transformed into a variety of arylboron compounds such as arylboronates, boronic acids, and trifluoroborates.

A new mechanism of La-catalyzed amidation of N-methylbenzylamine with p-chlorobenzaldehyde has been computationally proposed, where L₂La[NR₁R₂] (I) rather than previously proposed L₂La[OCHRNR₁R₂] (II) is the catalytically active species. Interestingly, the side-product alcohol acting as a proton relay to reduce reaction energy barrier could participate in the regeneration of I. Besides, DFT calculations suggest that an addition of alcohol additive into the initial reaction system could accelerate the reaction, which has been further verified by experiments.

Herein, we describe an efficient, practical photocatalytic deoxygenation/defluorination protocol for the synthesis of γ,γ-difluoroallylic ketones from commercially available aromatic carboxylic acids, triphenylphosphine, and α-trifluoromethyl alkenes. The protocol has good functional group tolerance and a broad substrate scope. Using this method, we accomplished the late-stage functionalization of several bioactive molecules.

A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.

The synthesis of 1,2,3-triazines and bicyclic tetrazoles from α-azido ketones is described. The common intermediate generated from lithiated trimethylsilyldiazomethane and α-azido ketones diverges depending on the steric bulk of the substituents. The formation of 1,2,3-triazines via a C–H insertion of alkylidene carbene to form 3-azidocyclopropene, followed by its rearrangement, is supported by density functional theory calculations. Tetrazole formation proceeds via a facile anionic [3 + 2] dipolar cycloaddition between a lithiated diazo moiety and an azido group facilitated by the chelation of a lithium ion.

C-centered radical cyclization under electrochemical conditions is a feasible strategy for constructing cyclic structures. Reported herein is the electrochemical synthesis of highly functionalized 1-naphthols using alkynes and 1,3-dicarbonyl compounds by (4 + 2) annulation of C-centered radical. Electrolysis was conducted with Cp₂Fe as redox catalyst, thereby eliminating the use of oxidants and transition-metal catalysts. The synthesized 1-naphthol compounds showed good antitumor activity in vitro, and further studies indicated that compound 3bl induced tumor cell apoptosis.

Disruption of an aminotransferase family gene dtlA activated the production of a novel dimeric benzoic polyene acids (BPAs), named youssoufene A1 (1), along with four new (2–5, youssoufenes B1–B4) and a known (6) monomeric BPA in the marine-derived Streptomyces youssoufiensis OUC6819. The structures of 1–5 were elucidated by extensive spectroscopic and computational approaches. Youssoufene A1 (1) exhibited notably increased growth inhibition (MIC = 12.5 μg/mL) against multidrug resistant Enterococcus faecalis compared to monomeric structures (2–6).

A structurally constrained S,C,C-bridged triphenylamine was synthesized, and the corresponding radical cation was obtained as a hexachloroantimonate by chemical oxidation. An X-ray crystallographic analysis revealed an almost planar structure for this radical cation, which thus represents the first example of a planar, para-unsubstituted triphenylamine radical cation analogue with a sulfur bridge. The electronic properties of the radical cation were examined by UV–vis–NIR and ESR spectroscopy as well as DFT calculations.

The first enantioselective synthesis of five-membered N-heterocyclic allylboronates has been accomplished by a C–B bond-forming dearomatization of pyrroles using a copper(I) catalyst. This reaction involves the regio- and enantioselective addition of a borylcopper(I) species to pyrrole-2-carboxylates, followed by the diastereoselective protonation of the resulting copper(I) enolate to afford pyrrolidine-type allylboronates. The products are highly attractive reagents for the rapid construction of pyrrolidine derivatives that bear five consecutive stereocenters via subsequent allylboration/oxidation processes.

Stereoselective total synthesis of marine secondary metabolite penicitide A has been accomplished for the first time following a convergent approach. The salient feature of this study includes Horner–Wadsworth–Emmons (HWE) olefination, Evans methylations, Crimmins acetate aldol reaction, and cross olefin metathesis. Our synthetic study established the stereochemistry of unassigned C-10 and C-12 centers and also disclosed the absolute configurations of C-3 and C-5 stereocenters.

A mild and high yielding rearrangement of 1,3-disubstituted-1,3-dienes to 1,1,4-trisubstituted-1,3-dienes using a cobaloxime catalyst and a silane cocatalyst is reported. Chiral centers near the conjugated diene were not racemized. Deuterium labeling studies are consistent with a hydrogen atom transfer mechanism, and radical intermediates were found to be accessible due to the observed ring opening of a cyclopropane ring.

Lewis acid enables the electrophilic carbooxygenative cyclization of alkynols with N,O-aminals. The new process proceeds efficiently under very mild conditions via a pathway that is opposite to classical carbo-metalation. These reactions exhibit broad substrate generality and functional group compatibility, leading to a wide variety of 5–8-membered oxacycles bearing diverse functional groups. The cyclization products can be elaborated via simple functional group transformations to generate synthetically useful oxacycles.

Recently, a paper in this journal reported the isolation and structure determination of hypatulone A. Several features of the proposed structure and biosynthesis induced us to reexamine the compound’s NMR spectra. Now we propose a revised structure, confirm it with quantum computations, and suggest a reasonable radical-mediated biosynthetic pathway to the revised structure. Our work illustrates how both biosynthetic considerations and quantum computations can complement spectroscopic structure determination.