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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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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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.
The authors declare no competing interests.
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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