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

Nature Catalysis volume 8, pages 1188–1197 (2025)Cite this article

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Abstract

Established strategies for enantioselective hydroalkylation for C(sp3)–C(sp3) bond formation usually require prefunctionalized substrates as radical precursors in both transition-metal and photoenzymatic catalysis. Here, based on a sequential proton transfer/electron transfer strategy, we show a cooperative photoenzymatic system consisting of a flavin-dependent ‘ene’-reductase and an organophotoredox catalyst fluorescein (FI) to achieve atom-economic enantiodivergent hydroalkylation of electron-deficient C(sp3)–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 between FMNox and FI−•, while the stereoselectivity is controlled by ene-reductases through enantioselective hydrogen atom transfer. 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.

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Fig. 1: Different photoenzymatic modes for enantioselective hydrofunctionalization.
Fig. 2: Substrate scope and molecular docking results.
Fig. 3: Proposed catalytic cycle.
Fig. 4: Mechanistic experiments.
Fig. 5: Mechanistic studies.

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Data availability

Data relating to the materials and methods, experimental procedures, mechanistic studies and computational calculations, HPLC spectra and NMR spectra are available in the Supplementary Information or from the authors on reasonable request. The coordinates of QM/MM and DFT calculations and configurations for MD simulations are available via GitHub at https://github.com/calculations01/The-coordinates-of-QM-MM-and-DFT-calculations. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Key R&D Program of China (grant no. 2022YFA0912000 to Y.W.), the Center of Synthetic Biology and Integrated Bioengineering (grant nos. WU2022A006, WU2022A007 and WU2023A009 to Y.W.), the Research Center for Industries of the Future (grant number WU2022C032 to Y.W.) and National Natural Science Foundation of China (grant no. 22121001 to B.W.). We thank the Instrumentation and Service Center for Molecular Sciences at Westlake University for the assistance in measurement and data interpretation. We thank Y. Chen for the assistance with HRMS, Y. Chen for the assistance with circular dichroism, X. Lou for the assistance with TAS and D. Gu for the assistance with EPR.

Author information

Author notes

  1. These authors contributed equally: Jin Zhu, Qiaoyu Zhang, Tao Gu.

Authors and Affiliations

  1. School of Materials Science and Engineering, Zhejiang University, Hangzhou, China

    Jin Zhu

  2. School of Engineering, Westlake University, Hangzhou, China

    Jin Zhu, Tao Gu, Binbin Chen, Mingzhe Ma, Xiao Liu, Mingjie Ma & Yajie Wang

  3. State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Qiaoyu Zhang, Xiaoyu Wang & Binju Wang

  4. School of Life Science, Westlake University, Hangzhou, China

    Yajie Wang

  5. Westlake Center of Synthetic Biology and Integrated Bioengineering, Westlake University, Hangzhou, China

    Yajie Wang

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Contributions

J.Z. and Y.W. conceived and designed the overall project. J.Z. performed all synthetic experiments and wet mechanism experiments. T.G., X.L. and Mingzhe Ma created mutations. Q.Z. and X.W. carried out the computational studies and the calculation of absolute configuration (ECD) under the supervision of B.W. B.C. completed the calculation of redox potentials and Gibbs reaction energy (ΔG) for SET of Int. A. Mingjie Ma performed the purification of some GluER variants. J.Z., B.W. and Y.W. wrote the paper with input of all authors.

Corresponding authors

Correspondence to Binju Wang or Yajie Wang.

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Nature Catalysis thanks Qi Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Notes 1–14, Figs. 1–53 and Tables 1–17.

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This data file corresponds to and provides the source data for Supplementary Figs. 10–16, 18–22, 24–28 and 46–51.

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Zhu, J., Zhang, Q., Gu, T. et al. Atom-economic enantioselective photoenzymatic radical hydroalkylation via single-electron oxidation of carbanions. Nat Catal 8, 1188–1197 (2025). https://doi.org/10.1038/s41929-025-01434-2

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