Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids: Sceptrin, Ageliferin, Nagelamide E, Oxysceptrin, Nakamuric Acid, and the Axinellamine Carbon Skeleton

The dimeric pyrrole imidazole natural products are a growing class of alkaloids with exotic
connectivity, unique topologies, high nitrogen content, and exciting bioactivities. This full account traces
the evolution of a strategy that culminated in the first total syntheses of several members of this family,
including sceptrin, ageliferin, nagelamide E, nakamuric acid (and its methyl ester), and oxysceptrin. Details
on the fascinating conversion of sceptrin to ageliferin, which has been used to produce gram quantities of
this sensitive natural product, are provided. In addition, the first enantioselective total synthesis of sceptrin
and ageliferin are reported by programming the fragmentation of an oxaquadricyclane. A hallmark of our
approach to this family of alkaloids is the minimal use of protecting groups despite the presence of 10
nitrogen atoms in the target compounds. Thus, the fundamental chemistry of the 2-aminoimidazole
heterocycle was explored without masking its innate reactivity. Insights gained during these explorations
led to total syntheses of oxysceptrin and nakamuric acid and a successful construction of the carbon skeleton
of axinellamine.