Abstract
Multicomponent reactions—those where three or more substrates combine into a product—have been highly useful in rapidly building chemical building blocks of increased complexity1, but achieving this enzymatically has remained rare2,3,4,5. This limitation primarily arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates6. Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions7,8. However, making such processes enantioselective is highly challenging owing to the inherent difficulty in the stereochemical control of radicals9. Here we repurpose a thiamine-dependent enzyme10,11 through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials—aldehydes, α-bromo-carbonyls and alkenes—to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photocatalyst–enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 24 out of 33 examples achieving ≥97% enantiomeric excess.
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Data availability
All data are available in the main text or Supplementary Information, and from the Cambridge Crystallographic Data Centre (CCDC; http://www.ccdc.cam.ac.uk/structures/); crystallographic data are available free of charge under CCDC reference numbers 2345903 (4a), 2345905 (4b) and 2345907 (4ab).
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Acknowledgements
We thank D. Ye, Y. Wang and Z. Shi from NJU for sharing their equipment. We thank the financial support from the National Natural Science Foundation of China (22277053, 22122305, 21927814 and 223B2703), the National Key Research and Development Program of China (2022YFA0913000 and 2019YFA0405600), Natural Science Foundation of Jiangsu Province (BK20220760), Fundamental Research Funds for the Central Universities 0205/14380346, Excellent Research Program of Nanjing University (ZYJH004), and the Strategic Priority Research Program of Chinese Academy of Sciences (XDB0960201 and XDB0540200).
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Z.X. developed the system and performed most of the synthetic experiments. F.L. performed the protein mutagenesis. J.F. performed the theoretical calculations under the supervision of B.W. L.Y. and A.L. carried out the electron paramagnetic resonance measurements. Z.W., B.Z. B.C., H.P., Y.X. and C.W. assisted in the synthetic experiments and mechanistic investigations. Y.Z. performed the X-ray crystal structure analysis. X.H. and B.W. wrote the paper with input from all authors. X.H. coordinated and conceived of the project.
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Xing, Z., Liu, F., Feng, J. et al. Synergistic photobiocatalysis for enantioselective triple-radical sorting. Nature 637, 1118–1123 (2025). https://doi.org/10.1038/s41586-024-08399-5
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DOI: https://doi.org/10.1038/s41586-024-08399-5
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