In Nature, chiral natural products are almost ubiquitously produced in optically pure form as single, distinct stereoiesomers; however, on occasion Nature is known to produce enantiomerically opposite metabolites. Enantiomeric natural products can arise in Nature from a single species, or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers, however, many fascinating puzzles and stereochemical anomalies still remain. Our laboratory, in collaboration with Prof. Sachiko Tsukamoto’s laboratory at Kumamoto University and Prof. David H. Sherman’s laboratory at the University of Michigan, have been particularly interested in the biosynthesis of prenylated indole alkaloids, such as the Paraherquamides, Malbranchemaides, Notoamides and Stephacidins which share a common bicyclo[2.2.2]diazaoctane core. It is believed that this ring system arises biosynthetically, via an intramolecular Diels-Alder type of cycloaddition of an unactivated isoprene-derived vinyl group with an azadiene species generated from the cyclo-didpeptide progenitors. We have successfully completed total syntheses of Brevianamide B, Paraherquamide A, Paraherquamide B, VM55599, Pre-paraherquamide, Stephacidin A, Avrainvillamide, Stephacidin B, Marcfortine C, Versicolamide B, Malbrancheamide, Pre-malbrancheamide and Notoamides B-E. Our work in this field involves addressing the controversial questions surrounding the putative existence of enzymatic catalysis for the Diels-Alder cycloaddition reaction in secondary metabolic pathways. Recent work in this area will be presented with an emphasis on the insight gained from unraveling the biosynthesis of these agents, which led to the discovery and refinement of biomimetic total syntheses of several members of this family of prenylated indole alkaloids. In particular, we have focused on the interesting and as yet, unexplained quandary, that the respective enantiomers of Stephacidin A, and Notoamide B are produced by genetically related Aspergillus sp. obtained in both marine and terrestrial environments. Curiously, only the (+)-enantiomer of Versicolamide B is produced by these Aspergillus sp. whose biogenesis remains an enigma. We have also discovered that the reverse prenyl transferases in the producing fungi, show poor facial discrimination in the reverse prenylation of tryptophan.

Enantiomeric natural products: Synthesis, biogenesis and evolutionary origins

254th National Meeting (2017)

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