Steering oxygen-centred radicals with ground-state ene-reductases for enantioselective intermolecular hydroalkoxylations

Abstract

Enzymes are emerging as promising catalysts for selective radical transformations. However, non-natural radical-type enzymatic catalysis is currently limited to utilizing C-, N- and S-centred radical species. Alkoxy radicals are recognized as versatile intermediates with high reactivity, typically engaging in reactivity modes such as hydrogen atom transfer, β-scission processes and intramolecular addition to alkenes. Enantioselective intermolecular alkoxy radical addition to alkenes remained unknown. Here we develop a biocatalytic strategy based on engineered ene-reductases that facilitate the radical hydroalkoxylation of oxygen-centred radicals with alkenes. A single, ground-state ene-reductase adeptly controls the biocompatible generation of O-radicals, the follow-up intermolecular O-radical addition to alkenes and the final prochiral C-radical termination, achieving high chemo- and enantioselectivity (both enantiomers are obtained separately with different enzymes). Mechanistic experiments, including computational simulations, reveal that the radical enzymatic reaction initiates via a ground-state single-electron transfer and elucidate the origins of enantiodiscrimination of the overall reaction. The intermolecular addition of O-centred radicals to alkenes is a challenging endeavour in synthetic chemistry. Now ene-reductases are used to tame reactive O-radicals for intermolecular and enantioselective radical hydroalkoxylation involving a ground-state single-electron radical mechanism.