A fully integrated eco-friendly continuous synthesis of pharmaceutically relevant building blocks exploiting immobilized Rhodotorula rubra

Rhodotorula is a widespread yeast genus, easily found in soil, water, air, milk, and fruit juice. In particular, R. rubra has shown to possess the ability to selectively reduce prochiral ketones with an excellent enantiomeric excess.[1,2] In this project, we exploited a bioreactor with immobilized whole cells of R. rubra to efficiently produce a key building block for the synthesis of the antidepressant drug duloxetine, i.e., (S)-3-hydroxy-3-(thiophen-2-yl)propanenitrile, (S)-1 (Scheme 1). A NADES formed by glucose and choline chloride served both as co-solvent and and substrate for cofactor regeneration, avoiding the use of any organic co-solvent, thus decreasing the environmental impact of the protocol. Moreover, the continuous system allowed for an automated work-up and purification procedure, through an in-line extraction with ethyl acetate followed by l/l separation and removal of the unreacted substrate using polymer supported benzylamine. The optimized protocol allowed the obtainment of compound (S)-1 in only 60 minutes with >90% conversion and >99% e.e. The protocol resulted to be versatile and was successfully used for the enantioselective reduction of different β-ketonitriles in gram scale.