Asymmetric Access to δ-Hydroxy α-Amino Acids Bearing Two Adjacent Stereocenters from Inert Allylic Alcohols Via Cu/Ru Relay Catalysis.

Abstract

Herein, we developed an efficient Cu/Ru relay catalytic system to achieve an asymmetric cascade reaction through merging hydrogen-borrowing and asymmetric Michael addition between inert allylic alcohols and ketoimine ester, enabling the efficient synthesis of biologically relevant chiral α-amino δ-hydroxy acid derivatives bearing two vicinal tertiary stereocenters in good yields with high diastereoselectivity and excellent enantioselectivity. This operationally simple and scalable protocol features excellent atom- and step-economy, broad substrate tolerance, and redox-neutral conditions. The synthetic utility was further exemplified through gram-scale synthesis, diverse downstream derivatizations, and a streamlined formal synthesis of l-pyrrolysine. Mechanistic investigations identified the Michael addition as both the stereodetermining and rate-limiting step in the cascade sequence.