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Decarboxylative alkenylation

Nature volume 545, pages 213–218 (2017)Cite this article

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Abstract

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter1. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis2 being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

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Figure 1: Development of Ni- and Fe-catalysed decarboxylative alkenylation.
Figure 2: Substrate scope of decarboxylative alkenylation.
Figure 3: Total synthesis enabled by decarboxylative alkenylation.

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Acknowledgements

Financial support for this work was provided by Bristol-Myers Squibb and the NIH/NIGMS (GM118176). The Department of Defense (DoD) supported a predoctoral fellowship to J.T.E. (National Defense Science and Engineering Graduate Fellowship (NDSEG) Program), and the NIH supported a postdoctoral fellowship to L.R.M. (F32GM117816). We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; M. R. Ghadiri for access to preparative high-performance liquid chromatography equipment; M. Schmidt and E.-X. Zhang for discussions; and M. Yan for assistance in the preparation of the manuscript. We are grateful to LEO Pharma for the donation of fusidic acid and to R. Shenvi for providing Mn(dpm)3.

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Author notes

  1. Jacob T. Edwards and Rohan R. Merchant: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Jacob T. Edwards, Rohan R. Merchant, Kyle S. McClymont, Kyle W. Knouse, Tian Qin, Lara R. Malins & Phil S. Baran

  2. Discovery Chemistry, Bristol-Myers Squibb, 350 Carter Road, Hopewell, New Jersey, 08540, USA

    Benjamin Vokits & Scott A. Shaw

  3. Asymchem Life Science (Tianjin), Tianjin Economic-technological Development Zone, Tianjin, 300457, China

    Deng-Hui Bao, Fu-Liang Wei & Ting Zhou

  4. Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, 08903, New Jersey, USA

    Martin D. Eastgate

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Contributions

J.T.E., R.R.M. and P.S.B. conceived the work. J.T.E., R.R.M., K.S.M., K.W.K., L.R.M., T.Q., B.V., S.A.S., M.D.E. and P.S.B. designed the experiments and analysed the data. J.T.E., R.R.M., K.S.M., K.W.K., L.R.M., T.Q. and B.V. performed the experiments. D.-H.B., F.-L.W. and T.Z. performed mole-scale experiments. P.S.B. wrote the manuscript. J.T.E., R.R.M., K.W.M. and K.W.K. assisted in writing and editing the manuscript.

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Correspondence to Phil S. Baran.

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Edwards, J., Merchant, R., McClymont, K. et al. Decarboxylative alkenylation. Nature 545, 213–218 (2017). https://doi.org/10.1038/nature22307

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