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

Nat Chem. 2015 Aug;7(8):641-5. doi: 10.1038/nchem.2281. Epub 2015 Jun 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / biosynthesis*
  • Catalysis
  • Cycloaddition Reaction
  • Dimerization
  • Models, Molecular

Substances

  • paracaseolide A
  • 4-Butyrolactone

Associated data

  • PubChem-Substance/251963719
  • PubChem-Substance/251963720
  • PubChem-Substance/251963721
  • PubChem-Substance/251963722
  • PubChem-Substance/251963723
  • PubChem-Substance/251963724
  • PubChem-Substance/251963725
  • PubChem-Substance/251963726
  • PubChem-Substance/251963727
  • PubChem-Substance/251963728
  • PubChem-Substance/251963729
  • PubChem-Substance/251963730
  • PubChem-Substance/251963731
  • PubChem-Substance/251963732
  • PubChem-Substance/251963733
  • PubChem-Substance/251963734
  • PubChem-Substance/251963735
  • PubChem-Substance/251963736
  • PubChem-Substance/251963737
  • PubChem-Substance/251963738
  • PubChem-Substance/251963739
  • PubChem-Substance/251963740