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Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)–C(sp) cross-coupling of tertiary electrophiles with alkynes

Nature Chemistry volume 14, pages 949–957 (2022)Cite this article

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Abstract

In contrast with the well-established enantioconvergent radical C(sp3)–C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp3)–C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples). Key to the success is the rational design of chiral anionic N,N,N-ligands tailor-made for the computationally predicted outer-sphere radical group transfer pathway. This protocol provides a practical platform for the construction of chiral C(sp3)–C(sp/sp2/sp3) bonds, allowing for expedient access to an array of synthetically challenging quaternary carbon building blocks of interest in organic synthesis and related areas.

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Fig. 1: Motivation and design of Cu-catalysed enantioconvergent cross-coupling of racemic tertiary alkyl halides with terminal alkynes.
Fig. 2: Synthetic utility and mechanistic discussion.
Fig. 3: Model DFT study on the operative catalytic cycle.
Fig. 4: DFT calculations on enantioselectivity control.

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Data availability

Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, DFT calculations, HPLC spectra, NMR spectra and mass spectrometry are available in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 2074298 (44), 2074300 (55), 2074301 (79) and 2074302 (C1). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank the National Natural Science Foundation of China (grants nos. 21831002 and 22025103 to X.-Y.L., 21901106 to F.-L.W., 22001109 to Q.-S.G. and 21702182, 21873081 and 22122109 to X.H.), Guangdong Innovative Program (no. 2019BT02Y335 to X.-Y.L.), Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002 to X.-Y.L.), Shenzhen Special Funds (no. JCYJ20200109141001789 to X.-Y.L.), SUSTech Special Fund for the Construction of High-Level Universities (no. G02216303 to X.-Y.L.), Fundamental Research Funds for the Central Universities (no. 2020XZZX002-02 to X.H.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (no. SN-ZJU-SIAS-006 to X.H.), the State Key Laboratory of Clean Energy Utilization (no. ZJUCEU2020007 to X.H.) and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province (no. PSFM2021-01 to X.H.) for financial support. We appreciate the assistance of SUSTech Core Research Facilities with compound characterization. We also appreciate the support of the Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University. Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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Author notes

  1. These authors contributed equally: Fu-Li Wang, Chang-Jiang Yang, Ji-Ren Liu.

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

    Fu-Li Wang, Chang-Jiang Yang, Ning-Yuan Yang, Xiao-Yang Dong, Ruo-Qi Jiang, Xiao-Yong Chang, Dai-Lei Yuan, Yu-Shuai Zhang & Xin-Yuan Liu

  2. Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, China

    Ji-Ren Liu, Guo-Xiong Xu & Xin Hong

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

Corresponding authors

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

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Supplementary information

Supplementary Information

Supplementary Figs. 1–31 and Tables 1–7, experimental procedures, synthetic procedures, characterization data, density functional theory (DFT) calculations and mechanistic discussion.

Supplementary Data 1

Crystallographic data for compound 44; CCDC reference 2074298.

Supplementary Data 2

Crystallographic data for compound 55; CCDC reference 2074300.

Supplementary Data 3

Crystallographic data for compound 79; CCDC reference 2074301.

Supplementary Data 4

Crystallographic data for compound C1; CCDC reference 2074302.

Supplementary Data 5

Tables of energies and coordinates in XYZ format.

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Wang, FL., Yang, CJ., Liu, JR. et al. Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)–C(sp) cross-coupling of tertiary electrophiles with alkynes. Nat. Chem. 14, 949–957 (2022). https://doi.org/10.1038/s41557-022-00954-9

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