title: 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.
authors.affiliation: Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hoye
mesh_terms: D015107:4-Butyrolactone / Q000096:biosynthesis*; D002384:Catalysis; D061565:Cycloaddition Reaction; D019281:Dimerization; D008958:Models, Molecular
chemical_list: C569208:paracaseolide A; D015107:4-Butyrolactone