Imine reductase-catalyzed enantiodivergent synthesis of axially chiral alkylidene cyclohexane amines.

Axially chiral alkylidene cycloalkanes (ACACs) are valuable yet underexplored scaffolds, and biocatalytic access to their enantioenriched amine derivatives remains limited. Herein, we report an imine reductase (IRED)-catalyzed asymmetric reductive amination of 4-alkylidene cyclohexanones with primary amines for the enantiodivergent synthesis of axially chiral alkylidene cyclohexane amines. Upon enzyme screening and reaction condition optimization, it was found that the use of AtIRED and MeIRED afforded a variety of (S)- and (R)-configured amine products in up to 99% conversion and 99 : 1 enantiomeric ratio (er). The synthetic applicability of this approach was further demonstrated on a semipreparative scale, furnishing the desired products in 66-67% isolated yields and 98 : 2-99 : 1 er. The current work offers an efficient means to access axially chiral alkylidene cycloalkane amines and underscores the enormous prospect of IREDs in the stereoselective synthesis of amines with axial chirality.