Asymmetric Reduction of Cyclic Imines by Imine Reductase Enzymes in Non‐Conventional Solvents

Abstract The first enantioselective reduction of 2‐substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non‐conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22–84 %) and excellent S ‐enantioselectivities (up to >99 % ee ). Remarkably, the process can be performed at a 100 mM substrate loading, which, for the model compound, means a concentration of 14.5 g L −1 . A fed‐batch protocol was also developed for a convenient scale‐up transformation, and one millimole of substrate 1 a was readily converted into 120 mg of enantiopure amine ( S )‐ 2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large‐scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest.