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Site- and enantioselective allylic and propargylic C–H oxidation enabled by copper-based biomimetic catalysis

Nature Catalysis volume 8, pages 58–66 (2025)Cite this article

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Abstract

Methods for direct enantioselective oxidation of C(sp3)–H bonds will revolutionize the preparation of chiral alcohols and their derivatives. Enzymatic catalysis, which uses key metal-oxo species to facilitate efficient hydrogen atom abstraction, has evolved as a highly selective approach for C–H oxidation in biological systems. Despite its effectiveness, reproducing this function and achieving high stereoselectivity in biomimetic catalysts has proven to be a daunting task. Here we present a copper-based biomimetic catalytic system that achieves highly efficient asymmetric sp3 C–H oxidation with C–H substrates as the limiting reagent. A Cu(II)-bound tert-butoxy radical is responsible for the site-selective C–H bond cleavage, which resembles the active site of copper-based enzymes for C–H oxidation. The developed method has been successfully accomplished with good functional group compatibility and exceptionally high site- and enantioselectivity, which is applicable for the late-stage oxidation of bioactive compounds.

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Fig. 1: Highly selective sp3 C–H oxidation.
Fig. 2: Initial results on the selective sp3 C–H oxidation with C–H substrates as limiting reagents.
Fig. 3: Mechanistic investigations on the reactions in CH3CN and CF3CH2OH.
Fig. 4: Computational analysis.
Fig. 5: Substrate scope on the site- and enantioselective C–H oxidation.

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Data availability

Crystallographic data for the structures reported in this Article are available from the Cambridge Crystallographic Data Centre with the deposition number CCDC 2391309. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

Financial support was provided by the National Key R&D Program of China (grant 2021YFA1500100), the National Natural Science Foundation of China (grants 22331012, 91956202, 92256301 and 21821002), the Science and Technology Commission of Shanghai Municipality (grants 20JC1417000 and 21520780100) and the International Partnership Program (grant 121731KYS-B20190016) of the Chinese Academy of Sciences and the Research Grants Council of Hong Kong (HKUST 16300620 and 16302222). H.Z. thanks Y. Zhang for the EPR manipulation and analysis. G.L. acknowledges support from the Tencent Foundation through the New Cornerstone Science Foundation.

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Author notes

  1. These authors contributed equally: Honggang Zhang, Yibo Zhou, Tilong Yang.

Authors and Affiliations

  1. New Cornerstone Science Laboratory, State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Honggang Zhang, Yibo Zhou, Jingui Wu, Pinhong Chen & Guosheng Liu

  2. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China

    Tilong Yang & Zhenyang Lin

Authors
  1. Honggang Zhang
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Contributions

H.Z., Y.Z., J.W. and G.L. conceived the work and designed the experiments. H.Z. and Y.Z. performed the predominated laboratory experiments, and J.W. contributed partly. T.Y. and Z.L. conducted DFT calculation. H.Z., Y.Z., P.C., Z.L. and G.L. analysed the data and wrote the manuscript.

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Correspondence to Zhenyang Lin or Guosheng Liu.

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

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Supplementary information

Supplementary Information

Supplementary Figs. 1–14, Tables 1–5, methods and references.

Supplementary Data 1

DFT-calculated Cartesian coordinates.

Supplementary Data 2

X-ray structure of (S)-9.

Supplementary Data 3

checkCIF report.

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Zhang, H., Zhou, Y., Yang, T. et al. Site- and enantioselective allylic and propargylic C–H oxidation enabled by copper-based biomimetic catalysis. Nat Catal 8, 58–66 (2025). https://doi.org/10.1038/s41929-024-01276-4

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