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Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins

Abstract

Carbon–carbon bonds, including those between sp3-hybridized carbon atoms (alkyl–alkyl bonds), typically comprise much of the framework of organic molecules. In the case of sp3-hybridized carbon, the carbon can be stereogenic and the particular stereochemistry can have implications for structure and function1,2,3. As a consequence, the development of methods that simultaneously construct alkyl–alkyl bonds and control stereochemistry is important, although challenging. Here we describe a strategy for enantioselective alkyl–alkyl bond formation, in which a racemic alkyl electrophile is coupled with an olefin in the presence of a hydrosilane, rather than via a traditional electrophile–nucleophile cross-coupling, through the action of a chiral nickel catalyst. We demonstrate that families of racemic alkyl halides—including secondary and tertiary electrophiles, which have not previously been shown to be suitable for enantioconvergent coupling with alkyl metal nucleophiles—cross-couple with olefins with good enantioselectivity and yield under very mild reaction conditions. Given the ready availability of olefins, our approach opens the door to developing more general methods for enantioconvergent alkyl–alkyl coupling.

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Fig. 1: Transition-metal-catalysed enantioconvergent alkyl–alkyl cross-coupling reactions of racemic alkyl electrophiles.
Fig. 2: Enantioconvergent alkyl–alkyl cross-coupling of racemic secondary alkyl electrophiles with olefins.
Fig. 3: Enantioconvergent alkyl–alkyl cross-coupling of racemic tertiary alkyl electrophiles with olefins.
Fig. 4: Mechanism.

Data availability

The data that support the findings of this study are available within the paper, its Supplementary Information (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/structures; crystallographic data are available free of charge under CCDC reference numbers 1822790–1822793, 1839344–1839346 and 1861568).

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Acknowledgements

Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, R01–GM62871) and the Gordon and Betty Moore Foundation (Caltech Center for Catalysis and Chemical Synthesis). We thank L. M. Henling, D. G. VanderVelde and S. C. Virgil for assistance and discussions.

Reviewer information

Nature thanks C. Gosmini and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors

Contributions

Z.W. and H.Y. performed all experiments. Z.W. and G.C.F. wrote the manuscript. All authors contributed to the analysis and the interpretation of the results.

Corresponding author

Correspondence to Gregory C. Fu.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

This file contains: I. General Information; II. Catalytic Enantioconvergent Couplings; III. Effect of Reaction Parameters; IV. Functional-Group Compatibility; V. Derivatization of the Coupling Products; VI. Mechanistic Studies; VII. Assignment of Absolute Configuration; VIII. References; and IX. 1H NMR and 13C NMR Spectra; ee Analysis.

Supplementary Data

This zip file contains the Crystallographic Information Files.

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Wang, Z., Yin, H. & Fu, G.C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018). https://doi.org/10.1038/s41586-018-0669-y

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Keywords

  • Alkyl Electrophiles
  • Racemic Alkyl
  • Hydrosilicates
  • Nucleophile Electrophile
  • Enantiomeric Excess

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