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Copper-catalysed synthesis of chiral alkynyl cyclopropanes using enantioconvergent radical cross-coupling of cyclopropyl halides with terminal alkynes

Nature Synthesis (2024)Cite this article

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Abstract

Transition-metal-catalysed enantioconvergent cross-coupling reactions of highly reactive alkyl radicals often suffer from reduced chemoselectivity, mainly due to side reactions with closed-shell reactants. A strategy to overcome this challenge has yet to be identified, posing substantial limitations on the synthetic utility of this method. Here we report a method for enantioconvergent radical carbon–carbon cross-coupling of highly reactive cyclopropyl radicals with terminal alkynes, using redox state-tuned copper catalysis, under mild conditions. Key to this method is the use of hard chiral N,N,N-ligands in combination with Cu(II) salts of hard ligands/counterions, which results in elevated concentrations of Cu(II) species and thus enhanced cross-coupling reactions. This protocol not only exhibits a broad substrate scope across a wide range of both racemic cyclopropyl halide and terminal alkyne coupling partners but also provides access to useful yet synthetically challenging enantioenriched cyclopropane building blocks.

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Fig. 1: Motivation and design of enantioconvergent radical C–C cross-coupling of racemic cyclopropyl electrophiles.
Fig. 2: Substrate scopes of alkynes and racemic cyclopropyl bromides.
Fig. 3: Reaction development and substrate scopes for other racemic cyclopropyl halides.
Fig. 4: Synthetic utility for the construction of valuable enantioenriched cyclopropane building blocks.
Fig. 5: Mechanistic studies and proposals.
Fig. 6: Preliminary experimental results and rationale for redox-state-tuned copper catalysis.

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Data availability

All data are available in the main text and Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2264730 (20), 2267172 (78), 2267173 (86) and 2264731 (88). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support from the National Natural Science Foundation of China (numbers 22025103, 92256301 and 22331006 to X.-Y.L.; 22271133 to Q.-S.G.; 22201127 to L.L.), the National Key R&D Program of China (numbers 2021YFF0701604 and 2021YFF0701704, to X.-Y.L.), the Guangdong Innovative Program (number 2019BT02Y335, to X.-Y.L.), the Guangdong Major Project of Basic and Applied Basic Research (number 2023B0303000020, to X.-Y.L.), the New Cornerstone Science Foundation through the Xplorer Prize (to X.-Y.L.), the Shenzhen Science and Technology Program (numbers KQTD20210811090112004, to X.-Y.L. and Q.-S.G.; JCYJ20220818100600001, to X.-Y.L.), the Shenzhen Key Laboratory of Cross-Coupling Reactions (number ZDSYS20220328104200001, to X.-Y.L.), High-Level of Special Funds (number G03050K003, to X.-Y.L.) and the High-Level Key Discipline Construction Project (number G030210001, to X.-Y.L.) is gratefully acknowledged. We appreciate the assistance of SUSTech Core Research Facilities.

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  1. These authors contributed equally: Zeng Gao, Lin Liu.

Authors and Affiliations

  1. Shenzhen Key Laboratory of Cross-Coupling Reactions, Southern University of Science and Technology, Shenzhen, China

    Zeng Gao, Lin Liu, Ji-Ren Liu, Wang Wang, Ning-Yuan Yang & Xin-Yuan Liu

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

    Zeng Gao, Ji-Ren Liu, Wang Wang, Ning-Yuan Yang, Lizhi Tao, Zhong-Liang Li, Qiang-Shuai Gu & Xin-Yuan Liu

  3. Department of Chemistry, Great Bay Institute for Advanced Study and Guangdong Provincial Key Laboratory of Mathematical and Neural Dynamical Systems, Great Bay University, Dongguan, China

    Lin Liu

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Contributions

Z.G., L.L., W.W. and L.T. designed the experiments and analysed the data. Z.G., L.L., W.W. and N.-Y.Y. performed the experiments. J.-R.L. designed and performed the DFT calculations. L.L., Z.-L.L., Q.-S.G. and X.-Y.L. wrote the paper. Q.-S.G. and X.-Y.L. conceived and supervised the project.

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Correspondence to Qiang-Shuai Gu or Xin-Yuan Liu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–17 and Tables 1–13, experimental procedures, synthetic procedures, characterization data, density functional theory (DFT) calculations and mechanistic discussion.

Supplementary Data 1

Crystallographic data for compound 20; CCDC reference 2264730.

Supplementary Data 2

Crystallographic data for compound 78; CCDC reference 2267172.

Supplementary Data 3

Crystallographic data for compound 86; CCDC reference 2267173.

Supplementary Data 4

Crystallographic data for compound 88; CCDC reference 2264731.

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Gao, Z., Liu, L., Liu, JR. et al. Copper-catalysed synthesis of chiral alkynyl cyclopropanes using enantioconvergent radical cross-coupling of cyclopropyl halides with terminal alkynes. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00654-x

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