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A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling

Nature Chemistry volume 11, pages 1158–1166 (2019)Cite this article

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Abstract

Continued development of the Sonogashira coupling has made it a well established and versatile reaction for the straightforward formation of C–C bonds, forging the carbon skeletons of broadly useful functionalized molecules. However, asymmetric Sonogashira coupling, particularly for C(sp3)–C(sp) bond formation, has remained largely unexplored. Here we demonstrate a general stereoconvergent Sonogashira C(sp3)–C(sp) cross-coupling of a broad range of terminal alkynes and racemic alkyl halides (>120 examples) that are enabled by copper-catalysed radical-involved alkynylation using a chiral cinchona alkaloid-based P,N-ligand. Industrially relevant acetylene and propyne are successfully incorporated, laying the foundation for scalable and economic synthetic applications. The potential utility of this method is demonstrated in the facile synthesis of stereoenriched bioactive or functional molecule derivatives, medicinal compounds and natural products that feature a range of chiral C(sp3)–C(sp/sp2/sp3) bonds. This work emphasizes the importance of radical species for developing enantioconvergent transformations.

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Fig. 1: Motivation and design of catalytic enantioselective Sonogashira C(sp3)−C(sp) cross-couplings.
Fig. 2: Synthetic applications of the catalytic enantioselective Sonogashira cross-coupling.
Fig. 3: Mechanistic studies of the catalytic enantioconvergent Sonogashira cross-coupling.

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Data availability

All of the characterization data and experimental protocols are provided in this article and its Supplementary Information. Data are also available from the corresponding author on request.

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Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (grant nos. 21722203, 21831002 and 21801116), Shenzhen Special Funds (grant nos. JCYJ20170412152435366 and JCYJ20170307105638498) and Shenzhen Nobel Prize Scientists Laboratory Project (grant no. C17783101).

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Author notes

  1. These authors contributed equally: Xiao-Yang Dong, Yu-Feng Zhang, Can-Liang Ma, Qiang-Shuai Gu, Fu-Li Wang.

Authors and Affiliations

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

    Xiao-Yang Dong, Yu-Feng Zhang, Can-Liang Ma, Fu-Li Wang, Sheng-Peng Jiang & Xin-Yuan Liu

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

    Qiang-Shuai Gu & Zhong-Liang Li

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Contributions

X.-Y.D., Y.-F.Z., C.-L.M., Q.-S.G. and F.-L.W. designed the experiments and analysed the data. X.-Y.D., Y.-F.Z., C.-L.M., F.-L.W., Z.-L.L. and S.-P.J. performed the experiments. All authors participated in writing the manuscript. X.-Y.L. conceived and supervised the project.

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Correspondence to Xin-Yuan Liu.

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Dong, XY., Zhang, YF., Ma, CL. et al. A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019). https://doi.org/10.1038/s41557-019-0346-2

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