Design of a fully automated system for the synthesis of pharmaceutically relevant building blocks exploiting immobilized Rhodotorula rubra and new solvent systems

Rhodotorula, a widespread yeast genus, can be easily found in soil, water, air, milk, and fruit juice. In particular, R. rubra displayed the ability to selectively reduce prochiral ketones with an outstanding enantiomeric excess [1,2]. The aim of our work was the exploitation of a bioreactor made 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 choline chloride-glucose natural deep eutectic solvent (NADES) was employed with a dual function, as a co-solvent and as a source of glucose, fundamental for the cofactor regeneration. To develop a fully automated protocol for the production of (S)-1, an in-line purification procedure has been designed. Firstly, an in-line extraction of the desired product was performed with a flow stream of ethyl acetate followed by a liquid/liquid separation. A polymer supported benzylamine packed in a glass column and connected to the organic stream allowed the removal of the unreacted ketone thereafter. 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.