Steric-Adaptive Biocatalysis: Imine Reductase-Mediated Dynamic Kinetic Resolution for Atroposelective Synthesis of...

As an efficient and environmentally benign strategy, enzymatic catalysis has emerged with high reactivity and selectivity for atropisomeric structures. Atropisomeric biaryl amines are of great importance in drug development and asymmetric catalysis. However, substrates with steric hindrance are often poorly accepted by enzymes, as the immense pockets required are not commonly found in wild-type enzymes. In this work, an imine reductase (IRED)-catalyzed dynamic kinetic resolution (DKR) strategy is introduced for the synthesis of atropisomeric biaryl amines, especially those with bulky substitutions on (hetero)aryls, including naphthalene- and quinoline-containing biaryl scaffolds. A broad range of atropisomeric biaryl amines are obtained in up to 99% yield and 99% ee, enabled by the steric adaptability of IR-09. Besides, a borrowing hydrogen cascade system is explored to extend the construction of atropisomeric biaryl amines directly from racemic alcohols. Density functional theory (DFT) calculations and molecular dynamics (MD) simulations are carried out to elucidate the DKR process, selectivity of IR-09, and interactions between the sterically hindered substrates and residues within the enzyme.