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Lactonization as a general route to β-C(sp3)–H functionalization

Nature volume 577, pages 656–659 (2020)Cite this article

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An Author Correction to this article was published on 23 September 2020

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Abstract

Functionalization of the β-C–H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions1,2,3,4,5. Despite efforts for β-C–H functionalization in carbon–carbon and carbon–heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope6,7,8,9,10,11,12,13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C–H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed β-C(sp3)–H lactonization of aliphatic acids enabled by a mono-N-protected β-amino acid ligand. The highly strained and reactive β-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the β position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(iv) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.

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Fig. 1: β-C(sp3)–H functionalization.
Fig. 2: Aliphatic acid scope for β-C(sp3)–H lactonization.
Fig. 3: Gram-scale β-C(sp3)–H lactonization of Gemfibrozil with 1 mol% Pd and diverse transformations.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information files.

Change history

  • 23 September 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We acknowledge The Scripps Research Institute and the NIH (NIGMS, R01GM084019) for financial support.

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Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Zhe Zhuang & Jin-Quan Yu

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  1. Zhe Zhuang
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  2. Jin-Quan Yu
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Contributions

J.-Q.Y. conceived the concept. Z.Z. developed the lactonization reaction. J.-Q.Y. directed the project.

Corresponding author

Correspondence to Jin-Quan Yu.

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The authors declare no competing interests.

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Peer review information Nature thanks Michael Doyle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

This file contains general information, an experimental section, additional references, and 1H and 13C NMR spectra.

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Zhuang, Z., Yu, JQ. Lactonization as a general route to β-C(sp3)–H functionalization. Nature 577, 656–659 (2020). https://doi.org/10.1038/s41586-019-1859-y

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