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Diels–Alderase-free, bis-pericyclic, [4+2] dimerization in the biosynthesis of (±)-paracaseolide A

Nature Chemistry volume 7, pages 641–645 (2015)Cite this article

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Abstract

The natural product paracaseolide A is a tetracyclic dilactone containing six adjacent stereocentres. Its skeleton occupies a unique structural space among the >200,000 characterized secondary metabolites. Six different research groups have reported a chemical synthesis of this compound, five of which used a thermal, net Diels–Alder [4+2] cycloaddition and dehydration at 110 °C to access the target by dimerization of a simple butenolide precursor. Here, we report that this dimerization proceeds under much milder conditions and with a different stereochemical outcome than previously recognized. This can be rationalized by invoking a bis-pericyclic transition state. Furthermore, we find that spontaneous epimerization, necessary to correct the configuration at one key stereocentre, is viable and that natural paracaseolide A is racemic. Together, these facts point to the absence of enzymatic catalysis (that is, Diels–Alderase activity) in the cycloaddition and strongly suggest that a non-enzyme-mediated dimerization is the actual event by which paracaseolide A is produced in nature.

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Figure 1: Structure and previous syntheses of paracaseolide A.
Figure 2: Strategy and methods for the synthesis of paracaseolide A and a truncated (methyl-containing) analogue.
Figure 3: The stereochemical outcome of spontaneous butenolide dimerization.
Figure 4: Conversion of the exo-Diels-Alder product to the natural product.
Figure 5: Epimerization of the Diels-Alder adducts may occur spontaneously.

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Acknowledgements

T.W. acknowledges the support of a Wayland E. Noland Fellowship and a University of Minnesota Graduate School Doctoral Dissertation Fellowship. The computational aspects of this work were performed with hardware and software resources available through the University of Minnesota Supercomputing Institute (MSI). Some graphical images were created using CYLview25. We appreciate receiving guidance from a reviewer who encouraged us to explore in greater computational depth the Diels–Alder dimerization, which led to the identification of the fully symmetrical, bis-pericyclic transition-state structure. Financial support for the research was provided by the National Cancer Institute of the National Institutes of Health (NIH; CA76497). NMR spectra were recorded on an instrument purchased with support from the NIH Shared Instrumentation Grant programme (S10OD011952).

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  1. Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, 55455, Minnesota, USA

    Tao Wang & Thomas R. Hoye

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  1. Tao Wang
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T.W. and T.R.H. conceived and designed the experiments, analysed the data and co-wrote the paper. T.W. performed the experiments.

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Correspondence to Thomas R. Hoye.

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Supplementary information (PDF 6595 kb)

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Crystallographic data for compound 1b. (CIF 21 kb)

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Crystallographic data for compound 7b. (CIF 15 kb)

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Wang, T., Hoye, T. Diels–Alderase-free, bis-pericyclic, [4+2] dimerization in the biosynthesis of (±)-paracaseolide A. Nature Chem 7, 641–645 (2015). https://doi.org/10.1038/nchem.2281

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