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Enantioselective alkyl–alkyl coupling by Ni-catalysed asymmetric cross-hydrodimerization of alkenes

Nature Synthesis (2024)Cite this article

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Abstract

Saturated tertiary stereogenic carbon centres are common in small molecules and organic materials. Transition-metal-catalysed asymmetric alkyl–alkyl bond formation processes represent contemporary techniques for the straightforward and efficient construction of saturated tertiary stereogenic carbon centres. However, reaction modes for asymmetric alkyl–alkyl bond formation between sp3-hybridized carbon atoms, C(sp3)–C(sp3), are limited yet highly desirable. Here a mode for asymmetric alkyl–alkyl bond formation enabled by Ni-catalysed asymmetric alkyl–alkyl cross-coupling between alkenes has been developed to construct tertiary stereogenic carbon centres. Ni-catalysed asymmetric cross-hydrodimerization of N-acyl enamines and unactivated alkenes enables head-to-tail regioselectivity and excellent levels of chemo- and enantioselectivity. Notably, the reaction proceeds in the presence of both reducing and oxidizing reagents, rendering alkenes as the sole precursors to forge enantioselective alkyl–alkyl bonds. The exclusive head-to-tail cross-hydrodimerization of distinct alkenes opens the way to access saturated tertiary stereogenic carbon centres from alkenes.

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Fig. 1: Significance, reaction modes and rationale for metal-catalysed asymmetric C(sp3)–C(sp3) cross-coupling.
Fig. 2: Substrate scope.
Fig. 3: Synthetic application and mechanistic studies.
Fig. 4: Proposed mechanisms for the reaction.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2270526 (3a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

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Acknowledgements

Financial support from the National Natural Science Foundation of China (22171127, 21971101 and 22371115), the Guangdong Basic and Applied Basic Research Foundation (2022A1515011806), Department of Education of Guangdong Province (2022JGXM054), The Pearl River Talent Recruitment Program (2019QN01Y261), Shenzhen Science and Technology Innovation Committee (JCYJ20220530114606013 and JCYJ20230807093522044) and Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002) is sincerely acknowledged. This research is supported by the SUSTech-NUS Joint Research Program. We acknowledge the assistance of the SUSTech Core Research Facilities.

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  1. These authors contributed equally: Peng-Fei Yang, Han-Tong Zhao.

Authors and Affiliations

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

    Peng-Fei Yang, Han-Tong Zhao, Xiao-Yi Chen & Wei Shu

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Contributions

W.S. conceived and directed the project. P.-F.Y. discovered and developed the reaction. P.-F.Y., H.-T.Z. and X.-Y.C. performed the experiments and collected the data. W.S. and P.-F.Y. analysed the data and wrote the paper with contributions from other authors.

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Correspondence to Wei Shu.

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Nature Synthesis thanks Debabrata Maiti 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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Supplementary Information

Experimental details and Supplementary Sections I–XI, Figs. 1–9 and Tables 1–13.

Supplementary Data 1

Crystallographic data for compound 3a; CCDC reference 2270526.

Source data

Source Data Fig. 3

Statistical source data.

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Yang, PF., Zhao, HT., Chen, XY. et al. Enantioselective alkyl–alkyl coupling by Ni-catalysed asymmetric cross-hydrodimerization of alkenes. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00609-2

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