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Enantioselective synthesis of γ-butenolides through Pd-catalysed C5-selective allylation of siloxyfurans

Nature Synthesis volume 1, pages 641–648 (2022)Cite this article

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Abstract

Metal-catalysed asymmetric allylic alkylation reactions have played a pivotal role in the construction of chiral compounds. When applied to the synthesis of butenolides, a common moiety present in many biologically active compounds, this reaction has always provided the C3-allylated products and only traces of the C5-allylated analogues. Here we report a Pd-catalysed C5-selective method that provides direct and highly enantioselective (up to >99% e.e.) access to a wide range of substituted butenolides using 2-substituted allyl acetates as the allylic partner. Mechanistic studies supported by density functional theory calculations have shown that the C5-selectivity observed is the result of a steric constraint induced by the substituent on the central carbon of the π–allyl complex forcing the reactive dienolate intermediate to expose its C5-reactive centre. The practicality, scalability and synthetic utility of the process was demonstrated through the total synthesis of three O-terpenoidal natural products: excavacoumarin B, D and E.

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Fig. 1: Experimental screening and rationalization of the C5-selective allylation.
Fig. 2: Access to unsubstituted allylic groups.
Fig. 3: Total synthesis of excavacoumarins B, D and E.

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Data availability

The experimental data as well as the characterization data for all the compounds prepared during this study, including NMR spectra and HPLC traces, are provided in the Supplementary Information. Crystallographic data for one of the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. CCDC 2102893 (7). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Queen Mary University of London and Eli Lilly are acknowledged for financial support. We also gratefully acknowledge I. Abrahams for X-ray diffraction analysis, H. Toms for support and guidance in NMR analysis and J. Ciesielski and A. Martin at Eli Lilly for fruitful discussions. We dedicate this work to the memory of Prof. J. Tsuji.

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Authors and Affiliations

  1. Department of Chemistry, Queen Mary University of London, London, UK

    François Richard, Sidonie Aubert, Tania Katsina, Luuk Reinalda, David Palomas, Rachel Crespo-Otero & Stellios Arseniyadis

  2. Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada

    Jingjun Huang & David C. Leitch

  3. Centro de Investigación Lilly SA, Alcobendas-Madrid, Spain

    Carlos Mateos

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Contributions

F.R., S. Aubert and S. Arseniyadis conceived the project. F.R., S. Aubert, T.K. and L.R. conducted the experiments and analysed the data. F.R. conducted the synthesis of all three excavacoumarins. J.H. and D.C.L. designed and prepared the DMPDAB-Pd-MAH complex. R.C.-O. and D.P. conducted the computational studies. F.R., D.C.L., C.M. and S. Arseniyadis wrote the manuscript with input from all authors. S. Arseniyadis directed the project.

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Correspondence to Stellios Arseniyadis.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

All the data reported in the paper are available in the Supplementary Information file.

Supplementary Data 1

Crystallographic data for compound 7, CCDC 2102893.

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Richard, F., Aubert, S., Katsina, T. et al. Enantioselective synthesis of γ-butenolides through Pd-catalysed C5-selective allylation of siloxyfurans. Nat. Synth 1, 641–648 (2022). https://doi.org/10.1038/s44160-022-00109-1

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