Access to Axially Chiral Biaryl Benzylamines via Ancestral Enzyme-Enabled Reductive Amination Desymmetrization

Abstract

Axially chiral biaryl benzylamines are present in numerous natural products, pharmaceuticals, chiral ligands, and catalysts. However, the direct catalytic synthesis of these functional molecules using a robust strategy remains a formidable challenge. Reductive amination desymmetrization of biaryl dialdehydes offers a powerful approach for the construction of axially chiral biaryl benzylamines but suffers from extensive undesirable side reactions. Herein, we engineered ancestral imine reductases to enable reductive amination desymmetrization of biaryl dialdehydes, allowing the construction of a wide range of axially chiral biaryl benzylamines with up to 99% conversion and 99% enantiomeric excess (ee). The ratio of the product to byproducts was up to 97:3 and over 90:10 in most cases. This work presents an alternative strategy for accessing axially chiral biaryl benzylamines and will stimulate the development of associated bioactive molecules and catalysts/ligands.