Asymmetric Hydrogenation of 3H-Azepines via Catalytic Kinetic Resolution: Access to anti-Disubstituted Azepanes

Abstract

Azepanes are increasingly valued scaffolds in drug discovery, yet general asymmetric methods for their synthesis remain elusive. This limitation is particularly evident for polysubstituted derivatives bearing stereocenters remote from the nitrogen atom, for which asymmetric access is essentially absent. Here we report the first asymmetric hydrogenation of 3H-azepines, enabling direct access to anti-configured azepanes with excellent diastereo- and enantioselectivity (>20:1 dr, up to 99:1 er). The transformation is mediated by an iridium catalyst featuring a mixed-ligand system composed of a chiral phosphoramidite and an achiral phosphine. Mechanistic studies reveal an unusual sequential pathway in which an initial a reduction generates an N-protected intermediate with low enantioselectivity, that subsequently undergoes a highly selective catalytic kinetic resolution. This work provides a catalytic solution to the asymmetric synthesis of disubstituted azepanes and expands the scope of asymmetric hydrogenation to anti-selective outcomes beyond classical enantiofacial discrimination.