Asymmetric Synthesis of Alkyl Fluorides via Biocatalytic Reduction of α-Fluoroenones and α-Fluoroenoates

Abstract

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. Importantly, the different alkene geometries led 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 undergoing reduction, enabling mixtures of alkene geometries to be employed. The selectivity and substrate scope were rationalized using in silico substrate-enzyme molecular docking studies. The enantioenriched alkyl fluorides were elaborated via chemical transformations to access further functionalized building blocks for synthesis.