Cooperative Photoenzymatic Catalysis for Enantioselective Fluoroalkylation/Cyclization Cascade.

Due to the invaluable properties of organofluorine compounds, incorporating a fluorinated unit has become necessary in pharmaceuticals, agrochemicals, and materials. However, achieving asymmetric fluorination such as trifluoromethylation through chemo- or biocatalysis has been a synthetic challenge. Here, we introduce a unique cooperative photoenzymatic catalysis for the enantioselective fluoroalkylation/cyclization cascade. This method, utilizing the engineered flavin-dependent "ene"-reductases (EREDs) and an exogenous photocatalyst (PC), produces a variety of fluorinated cyclic ketones with high yield and enantioselectivity. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the cyclized products further enhances the synthetic applications of our method. The radical-trapping, spectroscopic, and kinetic studies have substantiated the interaction mode between the PC and the enzyme and demonstrated a cascade reaction mechanism involving a unique intermolecular addition of fluorinated radicals and a stereocontrolled intramolecular cyclization. Isotopic labeling experiments support flavin as the source of the hydrogen atom. Molecular dynamics simulations reveal that the binding interaction of the enzyme and the intermediate triggers the photoinduced enantioselective cyclization. This work underscores the potential of enzymes for the asymmetric synthesis of fluorinated compounds.