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A general copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling

Nature Synthesis volume 2, pages 430–438 (2023)Cite this article

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Abstract

The Michaelis–Becker reaction of H-phosphonates with alkyl halides represents an ideal means for synthesizing alkyl phosphorous compounds. However, the enantioconvergent conversion of racemic alkyl halides into α-chiral alkyl phosphorous compounds in this reaction is an insurmountable challenge because of the inherent SN2 mechanism. Here we disclose a copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling. Key to the success of this reaction is the use of multidentate chiral anionic ligands for enhancing the reducing capability of the copper catalyst to favour a stereoablative radical pathway over a stereospecific SN2-type process. Moreover, the ligand architecture is also able to assist the robust association of copper species with alkyl radicals over H-phosphonates, therefore exerting remarkable chemo- and enantioselectivity. This protocol covers a range of (hetero)benzyl-, propargyl- and α-aminocarbonyl alkyl bromides and chlorides. When allied with follow-up transformations, this method provides a versatile platform for valuable α-chiral alkyl phosphorous building blocks and drug leads.

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Fig. 1: Motivation and design of copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling.
Fig. 2: Synthetic utility and mechanistic discussion.

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Data availability

Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, HPLC spectra, NMR spectra and high-resolution mass spectrometry data are available in the Supplementary Information.

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Acknowledgements

We thank the National Key R&D Program of China (2021YFF0701604 and 2021YFF0701704, X.-Y.L.), the National Natural Science Foundation of China (22025103 and 21831002, X.-Y.L.), the Guangdong Innovative Program (2019BT02Y335, X.-Y.L.), the Guangdong Provincial Key Laboratory of Catalysis (2020B121201002, X.-Y.L.), the Shenzhen Science and Technology Program (KQTD20210811090112004, X.-Y.L.) and Shenzhen Special Funds (JCYJ20200109141001789, X.-Y.L.) for financial support. We thank the SUSTech Core Research Facilities for assistance with compound characterization.

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  1. These authors contributed equally: Li-Lei Wang, Huan Zhou, Yu-Xi Cao.

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Li-Lei Wang, Huan Zhou, Yu-Xi Cao, Chi Zhang, Yang-Qing Ren & Xin-Yuan Liu

  2. Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Zhong-Liang Li & Qiang-Shuai Gu

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Contributions

X.-Y.L. conceived and supervised the project. L.-L.W., H.Z., Y.-X.C., C.Z., Y.-Q.R., Z.-L.L. and Q.-S.G. designed and performed the experiments and analysed the data. X.-Y.L., and L.-L.W. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Xin-Yuan Liu.

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Nature Synthesis thanks Wei-Liang Duan, Choon-Hong Tan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Wang, LL., Zhou, H., Cao, YX. et al. A general copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling. Nat. Synth 2, 430–438 (2023). https://doi.org/10.1038/s44160-023-00252-3

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