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.