Noncanonical β-Amino Esters and Amides via Direct Asymmetric Reductive Amination of α,α-Disubstituted β-Ketoesters and Amides

A direct asymmetric reductive amination (DARA) of α,α-disubstituted β-amino esters and amides has been developed to access a key β-amino amide intermediate for the commercial synthesis of a COVID protease inhibitor. High-throughput experimentation was utilized to identify a commercial ruthenium BINAP complex as an optimal catalyst for this transformation and counterion effects were critical for enabling the chemoselective reduction in this DARA strategy. The protocol was employed to synthesize a variety of highly substituted noncanonical β-amino esters and amides in good yields and excellent enantioselectivities. An intermolecular functional group tolerance study revealed that many Lewis basic functionalities are tolerated under reaction conditions and mechanistic insight was gained from reaction profile monitoring, isotopic labeling experiments, precatalyst poisoning studies, and ketone/imine equilibrium experiments.