Photoenzymatic Conversion of Enamides to Enantioenriched Benzylic Amines Enabled by Visible-Light-Induced Single-Electron Reduction

The enantioselective reduction of enamides is an efficient and atom-economical way to construct chiral amine motifs. In contrast to transition-metal complex based asymmetric hydrogenation, an alternative biocatalytic way is more sustainable but remains unexploited. The challenge lies in the redox potential mismatch between the ground-state enzymes and abiotic enamide substrates. Herein, we report a photoenzymatic strategy, expanding the reaction repertoires of biocatalysts to a previously elusive enantioselective reduction of enamides for the synthesis of enantioenriched amines (with up to a 99:1 enantiomeric ratio). Mechanistic wet experiments and computational studies revealed that direct visible-light excitation of the hydroquinone state flavin cofactor enhances the reducing capacity of ene-reductases, thereby triggering a biocatalytic single-electron reduction process. Mild and green reaction conditions as well as broad functional group tolerance make this unnatural photoenzymatic protocol a practical complement to traditional chemocatalytic approaches.