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Enantio- and diastereoselective construction of vicinal C(sp3) centres via nickel-catalysed hydroalkylation of alkenes

Nature Catalysis volume 5, pages 1180–1187 (2022)Cite this article

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Abstract

In drug discovery, the proportion of aliphatic carbons (C(sp3)) and the presence of chiral carbons in organic molecules are positively correlated to their chance of clinical success. Although methods exist for the synthesis of chiral C(sp3)-rich molecules, they often are limited in scope, have poor modularity or are unsuitable for stereoselective synthesis using racemic reagents. The stereocontrol of vicinal C(sp3) centres is a particular challenge. Here we describe nickel-catalysed enantio- and diastereoselective hydroalkylation of internal alkenes with racemic alkyl bromides to selectively form one of the four possible stereoisomers. Because of its general and modular character, and its high functional group tolerance, we expect this approach to have wide applications in the stereoselective synthesis of C(sp3)-rich molecules.

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Fig. 1: Stereoselective C(sp3)–C(sp3) cross-coupling.
Fig. 2: Scope of nickel-catalysed enantio- and diastereoselective hydroalkylation.
Fig. 3: Synthetic applications and diversification of the chiral products.
Fig. 4: Mechanistic studies.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2165076 (3aa), 2165081 (3ab), 2118223 (3ad) and 2118224 (3af). 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 or from the authors. Raw NMR and HPLC data are also freely available in Zenodo: https://doi.org/10.5281/zenodo.6797372.

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Acknowledgements

This work is supported by the Swiss National Science Foundation (200021_181977). We thank R. Scopelliti (EPFL) and F. Fadaei Tirani (EPFL) for the determination of the X-ray crystal structure of compounds 3aa, 3ab, 3ad and 3af.

Author information

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, Chao Fan & Xile Hu

  2. Department of Chemistry, Indian Institute of Technology Tirupati, Tirupati, India

    Srikrishna Bera

Authors
  1. Srikrishna Bera
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  2. Chao Fan
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Contributions

S.B. and X.H. conceived the project. S.B. designed, optimized and studied the scope and mechanism of the synthetic method. C.F. contributed to the study of synthetic applications and to some characterization of the compounds. S.B. and X.H. prepared the manuscript, with input from C.F.

Corresponding author

Correspondence to Xile Hu.

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The authors declare no competing interests.

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Nature Catalysis thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Tables 1–8, Figs. 1–10 and references.

Supplementary Data 1

Crystallographic data for compound 3aa.

Supplementary Data 2

Crystallographic data for compound 3ab.

Supplementary Data 3

Crystallographic data for compound 3ad.

Supplementary Data 4

Crystallographic data for compound 3af.

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Bera, S., Fan, C. & Hu, X. Enantio- and diastereoselective construction of vicinal C(sp3) centres via nickel-catalysed hydroalkylation of alkenes. Nat Catal 5, 1180–1187 (2022). https://doi.org/10.1038/s41929-022-00894-0

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