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Non-Enzyme Dimerization Likely in Biosynthesis of Paracaseolide

Tao Wang, a graduate student working in the laboratory of Professor Thomas Hoye, has established [Nature Chemistry, June 2015 (doi: 10.1038/nchem.2281)] that a non-enzyme-mediated dimerization is likely involved in the biosynthesis of the natural product known as paracaseolide A (3), a secondary metabolite having an unprecedented carbon skeleton. More specifically, he has shown that the key Diels-Alder (DA) homodimerization (1→2) is sufficiently rapid as to be biosynthetically relevant.

Previous work from five other laboratories had effected the overall transformation of 1 to 3—a two-stage [4+2] dimerization/dehydration process—in a single reaction flask at 110°C. Moreover, in those studies, researchers had assumed that the initial (but unobserved) Diels-Alder dimer had the structure of 2-endo. This would require a seemingly difficult epimerization at C5 in order to be converted into 3. Tao found that the dimer could be formed at much lower temperature and that it possesses the unanticipated stereochemical relationship represented in 2-exo. Density functional theory calculations revealed that a C2-symmetric, bis-pericyclic transition state structure (TS) defines the lowest energy pathway leading from 1 to 2.

He also found that 2-exo spontaneously undergoes self-organocatalyzed H/D-exchange at C7c in CD3OD, an observation consistent with the need to achieve facile epimerization at C7c in 2-exo enroute to 3. Finally, by separating the individual enantiomers of 3, Tao showed that the natural sample of paracaseolide A is racemic—a fact incompatible with its formation by the action of a Diels–Alderase enzyme. "Collectively, these observations lend sub-stantial support to the idea that a spontaneous DA dimerization of the butenolide [1] is the key biosynthetic event leading to paracaseolide A.”1

1 “Diels–Alderase-free, bis-pericyclic, [4+2] dimerization in the biosynthesis of (±)-paracaseolide A”, Wang, T.; Hoye, T. R. Nature Chem. 2015, Advance online publication.