An N-oxide fragmentation/hydroxylamine oxidation/intramolecular 1,3-dipolar cycloaddition cascade efficiently converted an oxidized congener of akuammicine into the complex, hexacyclic architecture of the alsmaphorazine alkaloids. This dramatic structural change shows the chemical feasibility of our novel proposal for alsmaphorazine biogenesis. Critical to these endeavors was a marked improvement in our previously reported Zincke aldehyde cycloaddition approach to indole alkaloids, which permitted the gram-scale synthesis of akuammicine. The chemoselective oxidations of akuammicine leading up to the key rearrangement also generated several biogenetically related alkaloids of the alstolucine and alpneumine families.

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, β-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the tert-amino effect, a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift.