Atom-economic enantioselective photoenzymatic radical hydroalkylation via single-electron oxidation of carbanions

Established strategies for enantioselective hydroalkylation for C( sp ³ )–C( sp ³ ) bond formation usually require pre-functionalized substrates as radical precursors in both transition-metal and photoenzymatic catalysis. Based on a sequential proton transfer/electron transfer (PT/ET) strategy, here we show a cooperative photoenzymatic system consisting of a flavin-dependent ‘ene’-reductase (ER) and an organophotoredox catalyst fluorescein (FI) to achieve atom-economic enantiodivergent hydroalkylation of electron-deficient C( sp ³ )–H with olefins. Mechanistic studies revealed a pathway for radical intermediate formation via excited-state FI ^* -induced single-electron oxidation of carbanions under alkaline conditions. The overall catalytic efficiency is enhanced by the electron transfer (ET) between FMN _ox and FI ^-• , while the stereoselectivity is controlled by ERs through enantioselective hydrogen atom transfer (HAT). We anticipate that this mode of photoenzymatic catalysis will inspire new pathways for generating free radical intermediates and foster innovative strategies for achieving photoenzymatic new-to-nature reactions.