UC Berkeley

The synthesis of aconitine-type diterpenoid alkaloids and analogs thereof has been completed. The first chapter of this dissertation introduces the diterpenoid alkaloid natural products and seminal studies toward their synthesis. The second chapter details strategies used to construct the polycyclic scaffolds of these highly bridged molecules, including both previous synthetic work and our own total synthesis of weisaconitine D. The third chapter focuses on the biological activity of these natural products and synthesis of analogs thereof to enable structure–activity relationship studies. The final chapter details ongoing studies regarding the rearrangement of strained [3.1.1] bicycles for use in terpene synthesis.

Chapter 1 includes discussion of the classification and biological activity of these topologically complex natural products. Seminal syntheses by both Nagata and Wiesner of two relatively simple diterpenoid alkaloids, atisine and garryine, are discussed alongside Wiesner’s later synthesis of the more highly bridged talatisamine.

Chapter 2 details how the use of bond-network analysis can provide clues on how to put together these highly caged scaffolds. The efficacy of this approach is evaluated in the context of eight modern syntheses of hetidine- and hetisine-type diterpenoid alkaloids. Bond-network analysis is then applied to the retrosynthesis of the aconitine-type diterpenoid alkaloids, identifying key disconnections that were ultimately applied successfully in the total synthesis of weisaconitine D. Two late-stage bicyclization strategies—the originally planned meta-pi-arene photocycloaddition and an alternative Diels–Alder cycloaddition/Wagner–Meerwein rearrangement sequence—are discussed.

Chapter 3 includes further discussion of the biological activity of the aconitine-type diterpenoid alkaloids, focusing on their modulation of voltage-gated sodium ion channels. The effects of two representative compounds, aconitine and lappaconitine, were evaluated in collaboration with Dr. David Hackos of Genentech and used as the starting point for structure–activity relationship studies using simplified analogs of these diterpenoid alkaloids. The design and synthesis of these analogs is discussed.

Chapter 4 focuses on the synthesis and rearrangement of strained [3.1.1] bicycles as part of an ongoing effort to synthesize terpene natural products. Discussion includes synthetic progress toward the sesterterpene somaliensene A from carvone using a strategy featuring cyclization and deoxygenation, as well as toward the diterpene xishacorene B from verbenone using a strategy featuring rearrangement and ring expansion.