Nickel‐Catalyzed Regioselective and Enantioselective Olefin–Aldehyde Cross‐Couplings Toward Acyloin Isosteres

Abstract Bioisosteric replacement of ketones with three‐dimensional (3D) motifs, such as oxetanes and azetidines, has emerged as a powerful tool in molecular design, enabling access to novel chemical space with improved pharmacokinetic profiles. However, general methods for the asymmetric synthesis of stereocenters adjacent to these strained, 3D frameworks remain scarce. Here, we report a nickel‐catalyzed, enantioselective reductive cross‐coupling between aldehydes and four‐membered heterocyclic alkenes to construct α‐hydroxy ketones bioisosteres with high efficiency and selectivity. Guided by N ‐heterocyclic carbene (NHC) ligands, the reaction proceeds with broad functional group tolerance, affording enantioenriched products in yields of up to 94% and an enantiomeric ratio (e.r.) of 99.8:0.2. The protocol is particularly amenable to the synthesis of enantioenriched α‐hydroxy difluoromethylene alkanes. Mechanistic investigations revealed how strain‐enabled reactivity and ligand control govern chemo‐, regio‐, and stereoselectivity. The synthetic utility of the method is demonstrated through gram‐scale preparation and diverse downstream derivatizations, offering a versatile platform for accessing previously elusive classes of stereodefined bioisosteres.