Biocatalytic Asymmetric Synthesis of (S)‐1‐[3,5‐bis(trifluoromethyl)phenyl]ethanol by an Immobilized KRED in Batch and Flow Conditions

Abstract

AbstractBoth enantiomers of 1‐(3,5‐bis(trifluoromethyl)phenyl)‐ethanol (BTPE) constitute important building‐blocks for the synthesis of active pharmaceuticals ingredients (APIs). The reduction of 3’,5’‐bis(trifluoromethyl)acetophenone (BTAP) performed with soluble and immobilized ketoreductases (KREDs) can be considered as one of the most efficient routes to produce enantiopure BTPE. In the present work, a commercial KRED was employed as biocatalyst after undergoing immobilization processes and it proved to be extremely efficient in the asymmetric synthesis of (S)‐BTPE. The immobilization was studied on a set of different commercially available supports. The best results were obtained with samples immobilized via covalent interaction on short chain amino‐functionalized support. Two reaction parameters, temperature, and solvent were optimized in the biocatalytic reduction of BTAP in batch conditions. A 90 : 10 (v/v) 2‐propanol (IPA): water solvent system and 30 °C proved to be the best reaction conditions in terms of substrate conversion and easy recovery of the product by simple solvent evaporation. Biotransformations were then performed in a flow system under optimized reaction conditions obtaining with most samples complete conversion after 24 hours and excellent enantiomeric excess (>99.9 %). Finally, the reusability of the immobilized biocatalyst was successfully tested in five consecutive reaction cycles, demonstrating the potential of this approach.