Ni-Catalyzed asymmetric reduction of alpha-keto-beta-lactams via DKR enabled by proton shuttling

Chiral alpha-hydroxy-beta-lactams are key fragments of many bioactive compounds and antibiotics, and the development of efficient synthetic methods for these compounds is of great value. The highly enantioselective dynamic kinetic resolution (DKR) of alpha-keto-beta-lactams was realized via a novel proton shuttling strategy. A wide range of alpha-keto-beta-lactams were reduced efficiently and enantioselectively by Ni-catalyzed asymmetric hydrogenation, providing the corresponding alpha-hydroxy-beta-lactam derivatives with high yields and enantioselectivities (up to 92% yield, up to 94% ee). Deuterium-labelling experiments indicate that phenylphosphinic acid plays a pivotal role in the DKR of alpha-keto-beta-lactams by promoting the enolization process. The synthetic potential of this protocol was demonstrated by its application in the synthesis of a key intermediate of Taxol and (+)-epi-Cytoxazone.