Radical hydroazidation of alkene enabled by synergistic photobiocatalysis combining ene-reductase with an organophotocatalyst

The integration of biocatalysis with photocatalysis provides a powerful platform for accessing non-natural biotransformations. While diverse net-reductive photobiocatalysis has been achieved with ene-reductases (EREDs), the redox-neutral construction of C–N 3 (C-azide) bond remains an underexplored challenge. Herein, we develop a synergistic photobiocatalytic system comprising an ERED and an organic dye that enables the enantioselective hydroazidation of alkenes. Upon visible-light-excitation, the organic dye promotes the single-electron oxidation of NaN 3 to generate N 3 • radical. This radical is then trapped by alkene, and the ensuing prochiral radical is precisely terminated by enzyme-controlled hydrogen-atom transfer (HAT), affording enantioenriched alkyl azides in excellent yield (up to 99%) and enantioselectivity (up to > 99.5:0.5 e.r.). This method applies to a variety of substituted alkenes, part of which bear vicinal stereocenters. Mechanistic studies, including ultraviolet-visible absorbance measurements, and luminescence quenching experiments, suggest a synergistic effect among the enzyme-bound flavin, organophotocatalyst, as well as sodium azide and explain the origin of stereochemical control. This work establishes a new biocatalytic strategy for the formation of C–N 3 bonds and expands the synthetic potential of light-driven flavoproteins.