Enantioselective Synthesis of Sterically Hindered α‐Allyl‐α‐Aryl Lactams via Palladium‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

Abstract

AbstractThe Pd‐catalysed decarboxylative asymmetric allylic alkylation (DAAA) of sterically hindered α‐aryl,β‐amido allyl ester lactams has been developed. The key step in the synthesis of a range of α‐aryl lactam substrates for catalysis was a Pb‐mediated α‐arylation of a β‐amido allyl ester affording 14 novel examples of α‐aryl‐β‐amido allyl ester lactams in good yields (up to 80 %). The Pd‐catalysed DAAA was optimised with the 2,4,6‐trimethoxyphenyl‐containing substrate. Using (S,S)‐DACH‐phenyl Trost as the optimal chiral ligand, enantioselectivities of up to 82 % ee were obtained. A substrate scope of 11 examples of α‐aryl‐β‐amido allyl ester lactams showed that products containing the di‐ortho‐methoxy‐substituted phenyls and naphthyl groups gave rise to the highest ees, whereas products not bearing this substitution pattern showed lower enantioselectivities (<60 % ee). Transition states to rationalise the observed stereochemical outcome are proposed.