Asymmetric Synthesis of N‐Substituted γ‐Amino Esters and γ‐Lactams Containing α,γ‐Stereogenic Centers via a Stereoselective Enzymatic Cascade

Abstract

Abstractγ‐Amino esters and γ‐lactams containing α,γ‐stereogenic centers are widely used as chiral intermediates in various bioactive compounds, while their efficient synthesis remains a challenge. Herein, an enzymatic cascade reaction involving an ene reductase (ERED) and an imine reductase (IRED) for accessing to α,γ‐stereospecific γ‐amino esters and γ‐lactams from α,β‐unsaturated γ‐ketoesters has been developed. 21 EREDs and 13 IREDs have been identified with high activity and stereoselectivity toward various α,β‐unsaturated γ‐ketoesters and the corresponding chiral γ‐ketoesters, respectively. By employing suitable ERED and IRED, (1S,3S), (1S,3R), (1R,3S), and (1R,3R) stereoisomers of methyl 3‐(cyclopropyl amino) cyclohexane‐1‐carboxylate were obtained as a single stereoisomer in 63–72% yield, and (3R,5R)‐ and (3R,5S)‐1‐cyclopropyl‐3,5‐dimethylpyrrolidin‐2‐one and 1‐cyclopropyl‐3,5‐dipropylpyrrolidin‐2‐one were also prepared as a single stereoisomer in 60–65% yields. This study establishes an environmentally friendly enzymatic route for the synthesis of γ‐amino esters and γ‐lactams containing α,γ‐stereogenic centers.magnified image