Asymmetric Synthesis of Bulky N-Cyclopropylmethyl-1-aryl-1-phenylmethylamines Catalyzed by Engineered Imine Reductases.

Abstract

Enzymatic reduction of diphenylmethanimine derivatives has rarely been reported owing to their steric hindrance. Herein, imine reductase (IRED) from Nocardia cyriacigeorgica rationally engineered with an efficient strategy of focused rational iterative site-specific mutagenesis (FRISM) was selected for the reduction of a series of N-cyclopropylmethyl-1-aryl-1-phenylmethylimines. Two highly enantioselective IRED variants were identified, providing various bulky amine products with moderate to high yields and high ee values (up to >99%). This work provided an effective method to construct these important pharmaceutical intermediates.