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The case for a Diels-Alderase-free, bis-pericyclic, [4+2] dimerization in the biosynthesis of (±)-paracaseolide A
The natural product paracaseolide A is a tetracyclic dilactone containing six adjacent stereocenters. It has an unprecedented skeleton and occupies unique structural space among the >200,000 characterized secondary metabolites. Six different research groups have reported a chemical synthesis of t...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878989/ https://www.ncbi.nlm.nih.gov/pubmed/26201740 http://dx.doi.org/10.1038/nchem.2281 |
Sumario: | The natural product paracaseolide A is a tetracyclic dilactone containing six adjacent stereocenters. It has an unprecedented skeleton and occupies 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 stereocenter, is viable and that natural paracaseolide A is racemic. Together these facts point to the absence of enzymatic catalysis (i.e., 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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