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Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis

Nature Chemistry volume 13, pages 270–277 (2021)Cite this article

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A Publisher Correction to this article was published on 08 February 2021

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Abstract

Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centres, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here, we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalysed alkyl–alkyl coupling. This strategy enables the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional-group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-pregabalin, are demonstrated.

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Fig. 1: Strategies for enantioselective C(sp3)–C(sp3) cross-coupling.
Fig. 2: Synthetic applications.
Fig. 3: Mechanistic studies of the catalytic enantioselective C(sp3)–C(sp3) cross-coupling.

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Data availability

Crystallographic data for 3e′ and 4g′ have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2011678 (3e′) and CCDC 1971802 (4g′). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk. All other data supporting the findings of this study, including experimental procedures and compound characterization, NMR, HPLC and X-ray analyses are available within the Article and its Supplementary Information.

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Acknowledgements

This work is supported by the Swiss National Science Foundation. We thank F. Fadaei Tirani for the determination of the X-ray crystal structures of compounds 3e′ and 4g′.

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Author notes

  1. These authors contributed equally: Srikrishna Bera and Runze Mao.

Authors and Affiliations

  1. Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), ISIC-LSCI, Lausanne, Switzerland

    Srikrishna Bera, Runze Mao & Xile Hu

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  1. Srikrishna Bera
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  2. Runze Mao
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  3. Xile Hu
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Contributions

S.B. and X.H. conceived the project. S.B. designed and optimized the synthetic method. S.B. and R.M. studied the scope, application and mechanism. All authors analysed the data and co-wrote the manuscript. X.H. directed the research.

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Correspondence to Xile Hu.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary information including optimization of reaction conditions (Supplementary Tables 1–6), general procedures, functional group transformations, mechanistic investigations, crystallography details, NMR spectra of compounds, references.

Supplementary Data 1

Compound 3e′.

Supplementary Data 2

Compound 4g′.

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Bera, S., Mao, R. & Hu, X. Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis. Nat. Chem. 13, 270–277 (2021). https://doi.org/10.1038/s41557-020-00576-z

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