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

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. Access through

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7809–7812 (2007). Article  CAS  Google Scholar  * _CYLview, 1.0b_ (Université de Sherbrooke, 2009); http://www.cylview.org Download references 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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Chemistry, University of Minnesota, 207

Pleasant Street SE, Minneapolis, 55455, Minnesota, USA Tao Wang & Thomas R. Hoye Authors * Tao Wang View author publications You can also search for this author inPubMed Google Scholar *

Thomas R. Hoye View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS T.W. and T.R.H. conceived and designed the experiments, analysed the data

and co-wrote the paper. T.W. performed the experiments. CORRESPONDING AUTHOR Correspondence to Thomas R. Hoye. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary information (PDF 6595 kb) SUPPLEMENTARY INFORMATION Crystallographic data for COMPOUND 1B. (CIF 21 kb)

SUPPLEMENTARY INFORMATION Crystallographic data for COMPOUND 7B. (CIF 15 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *

Received: 21 January 2015 * Accepted: 07 May 2015 * Published: 22 June 2015 * Issue Date: August 2015 * DOI: https://doi.org/10.1038/nchem.2281 SHARE THIS ARTICLE Anyone you share the

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