Qiang-Shuai Gu

Chiral tertiary alcohols are ubiquitous structural motifs in pharmaceutical agents and bioactive molecules, as well as versatile building blocks in organic synthesis, yet general catalytic enantioselective routes to these compounds remain limited. Direct transition-metal-catalyzed enantioconvergent C-O cross-coupling of racemic tertiary alkyl halides with water would provide an attractive entry to these structures, but this strategy remains largely unexplored because water can deactivate metal catalysts and presents a formidable challenge for enantiocontrol. Herein, we report a copper-catalyzed enantioconvergent O-alkylation of water with racemic α-tertiary haloamides through a radical-polar crossover pathway. Central to this process is the use of chiral anionic N,N,N-ligands, which promote the formation of coordinatively saturated Cu(III) intermediates that undergo enantioselective outer-sphere nucleophilic substitution by water, thereby enabling direct C(sp³)-O bond formation. This method provides practical and complementary access to a broad range of enantioenriched, sterically congested tertiary alcohols under mild conditions with good functional-group compatibility. The synthetic utility of this protocol is further demonstrated by the efficient preparation of diverse chiral tertiary alcohol building blocks and by concise syntheses of pharmaceutically relevant molecules, including sofpironium bromide and (S)-oxybutynin.

α‐Fluoroalkyl‐substituted high‐valent sulfur motifs are important structural elements in fluorinated molecule design and exhibit broad application potential in diverse fields. However, access to S ‐stereogenic α‐fluoroalkyl S(IV/VI) compounds still relies largely on classical resolution, resulting in limited efficiency and selectivity. We herein report a copper‐catalyzed asymmetric radical C–S cross‐coupling that effectively tames highly reactive α‐fluoroalkyl radicals, enabled by a sequential stereodiscrimination–chirality transfer strategy, providing rapid access to S ‐chiral α‐fluoroalkyl sulfilimines. Integrated with downstream transformations, this reaction serves as a general and systematic platform for S ‐chiral α‐fluoroalkyl S(IV/VI) compounds. The synthetic utility of the method is demonstrated by gram‐scale synthesis and concise access to diverse chiral fluoroalkyl reagents and bioisosteres of sulfur‐containing drugs.

α‐Fluoroalkyl‐substituted high‐valent sulfur motifs are important structural elements in fluorinated molecule design and exhibit broad application potential in diverse fields. However, access to S ‐stereogenic α‐fluoroalkyl S(IV/VI) compounds still relies largely on classical resolution, resulting in limited efficiency and selectivity. We herein report a copper‐catalyzed asymmetric radical C–S cross‐coupling that effectively tames highly reactive α‐fluoroalkyl radicals, enabled by a sequential stereodiscrimination–chirality transfer strategy, providing rapid access to S ‐chiral α‐fluoroalkyl sulfilimines. Integrated with downstream transformations, this reaction serves as a general and systematic platform for S ‐chiral α‐fluoroalkyl S(IV/VI) compounds. The synthetic utility of the method is demonstrated by gram‐scale synthesis and concise access to diverse chiral fluoroalkyl reagents and bioisosteres of sulfur‐containing drugs.

Transition-metal-catalyzed cross-coupling is a central strategy for installing alkenyl groups. Conventional two-electron oxidative addition of alkenyl halides is typically stereoretentive and, therefore, often requires geometrically highly enriched (E)- or (Z)-alkenyl halides, making stereoconvergent asymmetric cross-coupling of (E/Z)-mixed feedstocks challenging. Here we report a stereoconvergent and enantioselective Cu-catalyzed C-S cross-coupling of alkenyl iodides and bromides with sulfenamides to afford S-chiral alkenyl sulfilimines via alkenyl-radical intermediates that erase the initial alkene geometric information. The reaction proceeds under visible-light-driven Cu/photoredox conditions or Cu-catalyzed aryl radical-mediated halogen-atom transfer (XAT) conditions, delivering enantioenriched products with high alkene stereoselectivity and enantioselectivity across a broad substrate scope. The method is scalable, and the resulting chiral alkenyl sulfilimines can be readily diversified into a range of S-chiral sulfur(VI)-containing motifs, providing modular access to otherwise difficult-to-access enantioenriched sulfur-stereogenic alkenyl scaffolds.

Chiral hydrazines are important building blocks in chiral drug molecules, N-amino peptides, and aza-heterocycles. The catalytic enantioconvergent N-alkylation of readily available hydrazine derivatives with various racemic alkyl halides offers a highly attractive route to chiral hydrazines. However, this process remains challenging due to the lack of efficient asymmetric catalytic systems and the difficulty in achieving regioselectivity at the N¹/N² positions of hydrazine derivatives. Herein, we demonstrate a general copper-catalysed enantioconvergent N-alkylation of hydrazine derivatives with racemic α-haloamides. This strategy provides a modular approach for the synthesis of diverse enantioenriched hydrazines with excellent regio- and enantioselectivity. The key to success lies in the development of a radical-polar crossover nucleophilic substitution process and the employment of suitable hydrazine nucleophiles. Furthermore, this method provides a versatile platform to access a series of enantioenriched aza-heterocycles through facile subsequent transformations. It also enables the stereodivergent synthesis of all four possible stereoisomers of N-amino dipeptides bearing two stereocenters, with excellent stereoselectivity.

Achieving high enantioselectivity in asymmetric catalysis, especially with very reactive species such as radicals, often comes at the expense of generality. Radicals with exceptionally high reactivity are typically unsuitable for existing asymmetric methodologies. Here we present a general catalytic approach to asymmetric radical cross-coupling that combines copper-catalysed enantioselective stereocentre resolution or formation with copper-mediated, chirality-transferring radical substitution. This sequential strategy enables the efficient coupling of over 50 distinct carbon-, nitrogen-, oxygen-, sulfur- and phosphorus-centred radicals, including highly reactive methyl, tert-butoxyl and phenyl radicals, yielding structurally diverse C-, P- and S-chiral compounds with outstanding enantioselectivity. Our method thus provides a unified platform for the synthesis of carbon, phosphorus and sulfur stereocentres, with important implications for the preparation of chiral molecules relevant to medicinal chemistry and related disciplines. Furthermore, this sequential stereodiscrimination and chirality transfer strategy offers a promising blueprint for the development of highly enantioselective methodologies applicable to other classes of highly reactive species beyond radicals.

Transition-metal-catalysed asymmetric multicomponent reactions with two similar substrates often suffer from the lack of strategies to control the chemo-, regio-, and stereoselectivity of these substrates due to the close similarity in the chemical structures and properties of each reagent. Here, we describe a Cu(I)-catalysed asymmetric radical 1,2-carboalkynylation of two different terminal alkynes and alkyl halides with high chemo-, regio-, and stereoselectivity by using sterically bulky chiral tridentate anionic N,N,P-ligands and modulating alkynes with different electronic properties to circumvent above-mentioned challenges. This method features good substrate scope, high functional group tolerance of two different terminal alkynes, and diverse alkyl halides, providing universal access to a series of useful axially chiral 1,3-enyne building blocks.