The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids

CONSPECTUS: Over the course of the past decade, our group has been intensely interested in achieving the laboratory synthesis of varied members of the coccinellid alkaloid family of natural products. These compounds, produced by varied species of ladybugs throughout the world as defensive agents, include several polycyclic members that can formally be considered as either monomeric or dimeric with architectures that contain between 3 and 7 ring systems along with an array of stereocenters. As a result of their fascinating structures, many groups have achieved syntheses of varied monomeric members using a variety of synthetic strategies and tactics. However, no efforts to synthesize any of the dimeric structures had been reported at the time we began our studies, and only a modest amount of study had been performed as relates to their biosynthesis, with little knowledge of how the larger structures might actually arise in Nature. In this Account, we provide an overview of our general synthetic considerations to achieve a global synthesis of the collection, efforts that have led to date to the formal and total synthesis of 12 different members, 4 at the dimer level. Critical was (1) the identification of a key, common intermediate to enable access to a large number of monomeric substructures in short order, (2) careful thinking as to how the larger structures might arise biosynthetically to fuel building block design, and (3) the development of several reaction cascades that rapidly assembled the majority of their molecular complexity in single-pot operations. Key discoveries in the program include the finding that when efforts to achieve intermolecular dimerizations fail with advanced intermediates, attempts to couple more functionalized fragments earlier and then fold them into the desired structure can be an effective strategy. We also highlight suggestive evidence that a non-natural isomer we originally prepared from one of those cascades may, in fact, be a natural product. And, in particular, we will focus on how two key cascades were developed, as a result of synthetic challenges at varied points in our explorations, which proved capable of forging multiple bonds, rings, and stereocenters in the target structures. One of these includes a designed event that combined 9 different chemical reactions in a single pot and may prove useful for the synthesis of other targets.

Automated summary

Over the past decade, the research group has been dedicated to achieving the laboratory synthesis of various members of the coccinellid alkaloid family of natural products and has successfully synthesized 12 different members, with 4 being dimeric. Key discoveries included the identification of a key common intermediate, careful consideration of biosynthetic processes to design building blocks, and the development of reaction cascades for rapid assembly of molecular complexity.