Cobalt-Catalyzed Asymmetric Reductive Coupling of Isocyanates with Tertiary Alkyl Halides for Sterically Bulky Chiral Amide Synthesis.

The ubiquity of amide bonds in pharmaceuticals, agrochemicals, natural products, and peptides underscores the enduring demand for efficient amide synthesis in organic chemistry. Nevertheless, the facile construction of sterically congested chiral amides bearing α-quaternary stereogenic centers remains a formidable synthetic challenge. Herein, we report a catalytic reductive addition strategy that leverages readily accessible and stable isocyanates for stereoselective carbon-carbon bond formation. Enabled by earth-abundant chiral cobalt catalysis, this method achieves the enantioconvergent amidation of racemic tertiary alkyl halides, delivering α-tetrasubstituted amides with sterically demanding quaternary stereocenters. By circumventing the use of organometallic reagents, this unprecedented enantioselective alkylative reductive addition accommodates a broad substrate scope, including structurally diverse isocyanates and α-chloro tertiary amides, while achieving exceptional enantioselectivity (up to 99% ee). Preliminary mechanistic studies demonstrate a radical addition mechanism that is operative in this reductive amidation process.