Engineering an Imine Reductase for Enantioselective Synthesis of Atropisomeric Amides

Atropisomeric amides possess unique axial chirality arising from the rotation-restricted C aryl –C amide bond and find broad application in bioactive molecules and asymmetric catalysis. However, catalytic asymmetric methods for their synthesis remain underdeveloped, with no biocatalytic approaches reported. Herein, we report the first efficient biocatalytic strategy for the atroposelective synthesis of atropisomeric amides via dynamic kinetic resolution using engineered imine reductases (IREDs). Structure-guided engineering of an IRED from Kutzneria albida provided a quadruple mutant (IRED-68-M4) capable of catalyzing the stereoconvergent synthesis of diverse napthamides and benzamides in high yields and excellent enantioselectivities (up to 98% yield, >99:1 er). Gram-scale synthesis of an axially chiral napthamide was also demonstrated. Moreover, protein X-ray crystallography and molecular modeling studies revealed the structural basis of the enhanced catalytic performance of the IRED-68-M4 variant.