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Enantioselective construction of remote tertiary carbon–fluorine bonds

Nature Chemistry volume 11, pages 710–715 (2019)Cite this article

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Abstract

The carbon–fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity. The development of catalytic, enantioselective methods to set stereocentres that contain a benzylic C–F bond is a rapidly evolving goal in synthetic chemistry. Although there have been notable advances that enable the construction of secondary stereocentres that contain both a C–F and a C–H bond on the same carbon, significantly fewer strategies are defined to access stereocentres that incorporate a tertiary C–F bond, especially those remote from pre-existing activating groups. Here we report a general method that establishes C–F tertiary benzylic stereocentres by forging a C–C bond via a Pd-catalysed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners, as well as the ability to install the stereocentres remotely from pre-existing functional groups.

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Fig. 1: Constructing chiral, non-racemic tertiary fluorides.
Fig. 2: Evaluation of alkene substrates to establish remote stereocentres and mechanistic studies.

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Data availability

All the characterization data and experimental protocols are provided in this article and its Supplementary Information. Data are also available from the corresponding author upon request.

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Acknowledgements

The authors acknowledge financial support from the National Institutes of Health (NIGMS RO1 GM063540). J.L. thanks the Shanghai institute of Organic Chemistry, Chinese Academy of Sciences (SIOC), for a postdoctoral fellowship. Q.Y. acknowledges Shanghai Jiao Tong University for a postdoctoral fellowship.

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Authors and Affiliations

  1. Department of Chemistry, The University of Utah, Salt Lake City, UT, USA

    Jianbo Liu, Qianjia Yuan & Matthew S. Sigman

  2. Department of Chemistry, University of California, Berkeley, CA, USA

    F. Dean Toste

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Contributions

J.L. and Q.Y. performed the experiments and analysed the data. J.L, F.D.T. and M.S.S. designed the experiments. M.S.S. prepared this manuscript with feedback from F.D.T. and J.L.

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Correspondence to Matthew S. Sigman.

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Liu, J., Yuan, Q., Toste, F.D. et al. Enantioselective construction of remote tertiary carbon–fluorine bonds. Nat. Chem. 11, 710–715 (2019). https://doi.org/10.1038/s41557-019-0289-7

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