Engineering Imine Reductase for the Synthesis of Pharmaceutically Relevant 1-Aminomethylbenzocycloalkanes via Dynamic Kinetic Resolution–Asymmetric Reductive Amination

Asymmetric synthesis of chiral 1-aminomethylbenzocycloalkanes remains challenging. Here, an imine reductase variant (IR215-L97F/L187Q/A239M) was identified, showing a 277-fold increase in the catalytic efficiency and enhanced stereoselectivity (>99% ee) for the synthesis of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane (a key intermediate of ivabradine). This variant enabled the synthesis of a range of different substituted chiral 1-aminomethylbenzocyclobutanes and one example of a 1-aminomethylbenzocyclohexane with up to >99% ee values and 89% isolated yield, providing an efficient protocol for accessing pharmaceutically valuable compounds.