Asymmetric total syntheses of (+)- and (−)-versicolamide B and biosynthetic implications

The Diels–Alder reaction is one of the most well-studied, synthetically useful organic transformations. Although it has been postulated that a significant number of naturally occurring substances arise by biosynthetic Diels–Alder reactions, rigorous confirmation of a mechanistically distinct natural Diels–Alderase enzyme remains elusive. Within this context, several related fungi within the Aspergillus genus produce a number of metabolites of opposite absolute configuration, including (+)- or (−)-versicolamide B. These alkaloids are hypothesized to arise via biosynthetic Diels–Alder reactions, implying that each Aspergillus species possesses enantiomerically distinct Diels–Alderases. In this paper, experimental validation of these biosynthetic proposals via deployment of the intramolecular hetero-Diels–Alder reaction as a key step in the asymmetric total syntheses of (+)- and (−)-versicolamide B is described. Laboratory validation of the proposed biosynthetic Diels–Alder construction, coupled with the secondary metabolite profile of the producing fungi, reveals that each Aspergillus species has evolved enantiomerically distinct indole oxidases, as well as enantiomerically distinct Diels–Alderases. Two closely related species of fungus each produce one enantiomer of the same natural product. The biomimetic synthesis of both enantiomers reported here supports the unusual conclusion that the two species have evolved to produce a pair of enantiomerically distinct enzymes.