Imine Reductase–Catalyzed Remote Stereocontrol for Enantiodivergent Synthesis of Cyclohexylidene‐Based Axially Chiral Amines

Abstract Cyclohexylidene‐based amines exhibit unique axial chirality arising from the restricted double bond and have shown great potential in medicinal chemistry. However, their asymmetric synthesis remains challenging due to the long distance between the chirally relevant groups. Herein, we report a highly efficient and asymmetric synthesis of cyclohexylidene‐based axially chiral amines from 4‐substituted cyclohexanones and primary amines catalyzed by imine reductases (IREDs). Enantiodivergent IREDs were identified to provide convenient access to both enantiomers of chiral products with high yields and enantioselectivity (up to 99% yield, 99:1 or 1:99 enantiomeric ratio). A gram‐scale synthesis of cyclohexylidene‐based amines was also achieved. Moreover, protein X‐ray crystallography and molecular modeling studies were conducted to provide structural insight into the remote stereocontrol of IREDs in generating cyclohexylidene‐based axial chirality.