The true creator is necessity, who is the mother of our invention. s Plato I UPAC defines chemoselectivity as "the preferential reaction of a chemical reagent with one of two or more different functional groups", a definition that describes in rather understated terms the single greatest obstacle to complex molecule synthesis. Indeed, efforts to synthesize natural products often become case studies in the art and science of chemoselective control, a skill that nature has practiced deftly for billions of years but man has yet to master. Confrontation of one or perhaps a collection of functional groups that are either promiscuously reactive or stubbornly inert has the potential to unravel an entire strategic design. One could argue that the degree to which chemists can control chemoselectivity pales in comparison to the state of the art in stereocontrol. In this Account, we hope to illustrate how the combination of necessity and tenacity leads to the invention of chemoselective chemistry for the construction of complex molecules.In our laboratory, a premium is placed upon selecting targets that would be difficult or impossible to synthesize using traditional techniques. The successful total synthesis of such molecules demands a high degree of innovation, which in turn enables the discovery of new reactivity and principles for controlling chemoselectivity. In devising an approach to a difficult target, we choose bond disconnections that primarily maximize skeletal simplification, especially when the proposed chemistry is poorly precedented or completely unknown. By choosing such a strategysrather than adapting an approach to fit known reactionssinnovation and invention become the primary goal of the total synthesis. Delivery of the target molecule in a concise and convergent manner is the natural consequence of such endeavors, and invention becomes a prerequisite for success.

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.

Microwave‐induced magic: There is a widely held conviction that the antiviral marine alkaloid ageliferin 1 arises biosynthetically from a Diels–Alder reaction which, although possible, has yet to materialize in the laboratory. A total synthesis of 1 from sceptrin is now reported that has led to a new hypothesis for how 1 and other dimeric pyrrole‐imidazole alkaloids might be formed in nature.

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau’amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels–Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments are described.

Gifted with novel chemical features and extraordinary biological activity, sceptrin has remained a prominent unanswered synthetic challenge since its characterization in 1981 by Faulkner and Clardy. A concise and practical solution to the myriad of chemical challenges posed by sceptrin is reported in this Communication. Thus, through a sequence involving rearrangement of an oxaquadricyclane, a new method for chemo- and regioselective halogenation, a mild sequence for 2-aminoimidazole formation, and careful synthetic choreography, (+/-)-sceptrin is obtained in a minimum of steps and in 24% overall yield from dimethyl acetylenedicarboxylate without a single use of chromatography.