Enantioselective Synthesis of Alkyl Fluorides via Biocatalytic Reduction

Here we report the first biocatalytic asymmetric synthesis of alkyl fluorides via reduction of α-fluoroenones and α-fluoroenoates using ene reductase enzymes. The reduction of a wide range of (Z) or (E)-α-fluoroenones was shown to proceed in high yield and selectivity using ene reductases, with the different alkene geometries leading to opposite enantiomers of the chiral fluoroalkane. The reaction could also be successfully extended to α-fluoroenoates to access enantioenriched α-fluoroesters with only the E-alkene isomers under-going reduction, enabling mixtures of alkene geometries to be employed. The selectivity and substrate scope were rationalized using in silico substrate-enzyme molecular docking studies.