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Copper-catalysed asymmetric cross-coupling reactions tolerant of highly reactive radicals

Nature Chemistry volume 18, pages 142–151 (2026)Cite this article

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Abstract

Achieving high enantioselectivity in asymmetric catalysis, especially with very reactive species such as radicals, often comes at the expense of generality. Radicals with exceptionally high reactivity are typically unsuitable for existing asymmetric methodologies. Here we present a general catalytic approach to asymmetric radical cross-coupling that combines copper-catalysed enantioselective stereocentre resolution or formation with copper-mediated, chirality-transferring radical substitution. This sequential strategy enables the efficient coupling of over 50 distinct carbon-, nitrogen-, oxygen-, sulfur- and phosphorus-centred radicals, including highly reactive methyl, tert-butoxyl and phenyl radicals, yielding structurally diverse C-, P- and S-chiral compounds with outstanding enantioselectivity. Our method thus provides a unified platform for the synthesis of carbon, phosphorus and sulfur stereocentres, with important implications for the preparation of chiral molecules relevant to medicinal chemistry and related disciplines. Furthermore, this sequential stereodiscrimination and chirality transfer strategy offers a promising blueprint for the development of highly enantioselective methodologies applicable to other classes of highly reactive species beyond radicals.

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Fig. 1: Sequential stereodiscrimination and chirality transfer strategy for asymmetric transformations of highly reactive radicals.
Fig. 2: Inspirations and reaction development.
Fig. 3: Synthetic utility and mechanistic studies.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information (experimental procedures, characterization data and DFT calculations). Crystallographic data are also available free of charge from the Cambridge Crystallographic Database Centre (CCDC) under CCDC reference numbers 2289793 (for M1), 2375977 (for (R)-S5), 2375978 (for 9), 2375976 (for 20), 2289792 (for 36), 2289795 (for 46) and 2289794 (for 57). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We appreciate the assistance of SUSTech Core Research Facilities. We acknowledge the financial support from the National Natural Science Foundation of China (grant nos. 22025103, 92256301 and 22331006 to X.-Y.L., 22271133 to Q.-S.G., and W2512004, 22122109 and 22271253 to X.H.), the National Key R&D Program of China (grant nos. 2021YFF0701604 to X.-Y.L., 2022YFC3401104 to Z.D. and 2022YFA1504301 to X.H.), Guangdong Innovative Program (grant nos. 2019BT02Y335 to X.-Y.L. and 2021ZT09C278 to Z.D.), the Guangdong Major Project of Basic and Applied Basic Research (grant no. 2023B0303000020 to X.-Y.L. and Z.D.), Shenzhen Science and Technology Program (grant nos. KQTD20210811090112004 to X.-Y.L. and Q.-S.G., JCYJ20220818100600001 to X.-Y.L., JCYJ20220818100604009 to J.-B.T. and 20220814231741002 to Z.D.), the New Cornerstone Science Foundation through an XPLORER PRIZE (to X.-Y.L.), High-Level of Special Funds (grant no. G03050K003 to X.-Y.L.), High-Level Key Discipline Construction Project (grant no. G030210001 to X.-Y.L. and Q.-S.G.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (grant no. SN-ZJU-SIAS-006 to X.H.), CAS Youth Interdisciplinary Team (grant no. JCTD-2021-11 to X.H.), the Fundamental Research Funds for the Central Universities (grant nos. 226-2022-00140, 226-2022-00224, 226-2023-00115 and 226-2024-00003 to X.H), the State Key Laboratory of Clean Energy Utilization (grant no. ZJUCEU2020007 to X.H.), the State Key Laboratory of Physical Chemistry of Solid Surfaces (grant no. 202210 to X.H.), a Leading Innovation Team grant from the Department of Science and Technology of Zhejiang Province (grant no. 2022R01005 to X.H.) and the Open Research Fund of the School of Chemistry and Chemical Engineering of Henan Normal University (grant no. 2024Z01 to X.H.). Computational studies were supported by the Center for Computational Science and Engineering of Southern University of Science and Technology and the high-performance computing system at the Department of Chemistry, Zhejiang University.

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Author notes

  1. These authors contributed equally: Li-Wen Fan, Jun-Bin Tang, Li-Lei Wang, Zeng Gao, Ji-Ren Liu.

Authors and Affiliations

  1. Shenzhen Grubbs Institute, Department of Chemistry, and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China

    Li-Wen Fan, Jun-Bin Tang, Li-Lei Wang, Zeng Gao, Ji-Ren Liu, Yu-Shuai Zhang, Dai-Lei Yuan, Li Qin, Yu Tian, Zhi-Chao Chen, Fu Liu, Jin-Min Xiang, Pei-Jie Huang, Wei-Long Liu, Chen-Yu Xiao, Cheng Luan, Zhong-Liang Li, Zhe Dong, Qiang-Shuai Gu & Xin-Yuan Liu

  2. Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, China

    Li-Wen Fan, Yu-Shuai Zhang, Dai-Lei Yuan, Chen-Yu Xiao, Cheng Luan & Qiang-Shuai Gu

  3. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China

    Ji-Ren Liu & Xin Hong

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Contributions

L.-W.F., J.-B.T., L.-L.W. and Z.G. designed the experiments and analysed the data. L.-W.F., J.-B.T., L.-L.W., Z.G., Y.-S.Z., D.-L.Y., L.Q., Y.T., Z.-C.C., F.L., J.-M.X., P.-J.H., W.-L.L., C.-Y.X., C.L. and Z.-L.L. performed the experiments. J.-R.L. and X.H. designed the DFT calculations, and J.-R.L. performed the calculations. X.H., Z.D., Q.-S.G. and X.-Y.L. wrote the paper. Z.D., Q.-S.G. and X.-Y.L. conceived and supervised the project.

Corresponding authors

Correspondence to Xin Hong, Zhe Dong, Qiang-Shuai Gu or Xin-Yuan Liu.

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Supplementary Information

Supplementary Figs. 1–32, Tables 1–22, Experimental procedures, Synthetic procedures, Characterization data, Density functional theory calculations and Mechanistic discussion.

Supplementary Data

Cartesian coordinates of computed species.

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Fan, LW., Tang, JB., Wang, LL. et al. Copper-catalysed asymmetric cross-coupling reactions tolerant of highly reactive radicals. Nat. Chem. 18, 142–151 (2026). https://doi.org/10.1038/s41557-025-01970-1

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