Atroposelective Construction of Tetra‐ ortho ‐Substituted Dibenz[ c , e ]azepines Using an Engineered Imine Reductase

ABSTRACT Atropisomeric dibenz[ c , e ]azepines are privileged scaffolds in asymmetric synthesis, medicinal chemistry, and materials science, yet their atroposelective preparation remains challenging due to the difficulty of controlling axial chirality while constructing a strained medium‐sized ring. Tetra‐ ortho ‐substituted dibenz[ c , e ]azepines are especially elusive, with no catalytic asymmetric method reported owing to extreme steric hindrance. Here, we report the first biocatalytic strategy for the atroposelective synthesis of these congested bridged biaryls, employing an engineered imine reductase (IRED) that catalyzes a sequential inter‐ and intramolecular reductive amination cascade. Structure‐guided directed evolution of an IRED from Streptomyces tricolor provided a triple mutant (IRED‐04‐M3) that delivers various tetra‐ ortho ‐substituted dibenz[ c , e ]azepines in high yields with excellent atroposelectivity (up to 97% yield, >99:1 er) by dynamic kinetic resolution. Gram‐scale preparation was also demonstrated. Mechanistic studies and molecular dynamics simulations provide insight into the cascade reaction and stereocontrol exerted by the engineered enzyme.