Enantioconvergent Assembly of Chiral Difluoromethyl Stereocenters by Nickel-Catalyzed Reductive Cross-Coupling

Abstract The catalytic asymmetric construction of C(sp3)–CF2H stereocenters remains a longstanding challenge in synthetic and medicinal chemistry. Herein, we report a nickel-catalyzed enantioconvergent reductive cross-coupling strategy that enables efficient access to chiral difluoromethyl-containing molecules from readily available starting materials. Central to this approach is a modular difluoromethyl alkyl triflate reagent, which can be prepared in two steps from simple aliphatic aldehydes and serves as an effective CF2H radical precursor under reductive nickel catalysis. In the presence of a rationally developed BiOx ligand, the reaction proceeds under mild conditions with broad substrate scope, good functional-group compatibility, and high enantioselectivity. The synthetic utility of this method is further demonstrated through late-stage asymmetric difluoroalkylation of complex bioactive molecules and concise access to chiral difluoromethyl analogues of a DprE1 inhibitor. This work establishes a general platform for catalytic asymmetric radical difluoroalkylation and provides promising opportunities for the discovery of chiral fluorinated pharmaceuticals.