Biocatalytic atroposelective synthesis of heterobiaryls and heterobiaryl N-oxides via dynamic kinetic resolution†

Abstract

Heterobiaryl and heterobiaryl N-oxide atropisomers are important scaffolds in various chiral ligands, organocatalysts, and bioactive molecules. Here, we report a highly efficient biocatalytic route for the asymmetric synthesis of axially chiral heterobiaryl amines and heterobiaryl N-oxide amines via dynamic kinetic resolution (DKR). This novel DKR process features a racemization strategy promoted by forming a labile transition state via non-covalent interaction, coupled with a stereoselective reduction catalyzed by engineered imine-reductases (IREDs). Directed evolution of an IRED from Streptomyces sp. GF3546 provided two variants: S-IRED-Ss-M14 is superior for synthesizing diverse heterobiaryl amines, especially the ones containing multiple heteroatoms, and S-IRED-Ss-M16 is efficient for constructing heterobiaryl N-oxide amines. Both engineered IRED variants showed a broad substrate scope with a high level of yield and enantioselectivity (up to 98% yield and >99 : 1 enantiomeric ratio). This evolvable IRED-catalyzed DKR represents a promising solution for the atroposelective preparation of challenging axially chiral heterocyclic atropisomers.