Process Development of Enantioselective Imine Reductase-Catalyzed Syntheses of Pharmaceutically Relevant Pyrrolidines

Process development and optimization for an enzymatic reduction of 2-aryl-substituted pyrrolines to enantioselectively access the corresponding pyrrolidines have been carried out. Such chiral pyrrolidines are of high pharmaceutical interest and represent structural subunits in, e.g., larotrectinib and MSC2530818. This work enables access to the heterocyclic amine products with full conversion (>99%), excellent enantioselectivity (>99% ee), and good to high yield (up to 91%) in the presence of a readily available recombinant Escherichia coli-type whole-cell catalyst containing an imine reductase from Cupriavidus sp. HPC(L) and a glucose dehydrogenase in recombinant form. The developed processes utilizes cheap d-glucose as an economically favorable and nontoxic reducing agent and runs at a substrate loading of 18 g/L, which is also in an attractive range for larger-scale operations.