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

Tao Wang, Thomas R. Hoye

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)641-645
Number of pages5
JournalNature Chemistry
Volume7
Issue number8
DOIs
StatePublished - Aug 25 2015

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