Chemoenzymatic Stereoselective Synthesis of Substituted γ‐ or δ‐lactams with Two Chiral Centers via Transaminase‐catalysed Dynamic Kinetic Resolution

Abstract

AbstractThe biocatalytic stereoselective synthesis of lactams with two chiral centers by a dynamic kinetic resolution strategy is demonstrated. Five transaminases were examined for the transamination of chemically synthesized substituted γ‐ or δ‐keto esters. The application of (R)‐ and (S)‐selective enzymes led to the corresponding chiral amines with moderate to high diastereomeric ratios and excellent enantiomeric excess, followed by the formation of γ‐ or δ‐lactams in some cases. Reaction conditions including pH, co‐solvent and ratio of amine donor vs. acceptor were optimised. The stereoselective biotransaminations were performed at semi‐preparative scale, successfully generating the corresponding lactams or amine in 46–70 % isolated yields, up to 99 : 1 diastereomeric ratios and >99 % ee values. This study represents a promising approach to the biocatalytic synthesis of important γ‐ and δ‐lactams with two chiral centers.