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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年7月4日

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  • Bin Chen,
  • Qiaoyu Zhang,
  • Jinhai Yu,
  • Beibei Zhao,
  • Ran Ge,
  • Zihan Zhang,
  • Ding Luo,
  • Binju Wang,
  • Xiaoqiang Huang

摘要

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.