UC Berkeley

Diterpenoid alkaloids have long attracted significant interest from the synthetic community due to their intricate polycyclic architectures and diverse biological activities. Numerous members of this class exhibit therapeutic potential in the treatment of pain and other diseases. Among them, sulfonated diterpenoid alkaloids, such as aconicarmisulfonine A and aconapelsulfonine A, have been shown to exhibit remarkable analgesic activity in preliminary mouse studies. These findings render such compounds particularly attractive targets for the development of novel pain therapeutics, especially considering the growing interest in selectively targeting sodium channels for pain management. This two-part dissertation details our synthetic entry to this class of structurally complex natural products.In Part I, the relevant background of diterpenoid alkaloids is first presented. This is followed by the first total synthesis of aconicarmisulfonine A, which features the development of a photochemically enabled annulation sequence, a thermodynamically controlled intramolecular Mannich cyclization to access the aza-bicyclo[3.3.1]nonane core, and a late-stage oxidative strategy for the installation of the sulfonic acid functionality. This work not only establishes an efficient synthetic route to aconicarmisulfonine A but also provides a general platform for accessing structurally diverse sulfonated diterpenoid alkaloids.In Part II, a unified synthetic strategy toward various C20 diterpene alkaloids is described. Central to this approach is the identification of a scalable intermediate, previously employed in Part I, which can be repurposed for downstream diversification through an intramolecular Heck reaction. This strategy establishes a versatile platform for accessing napelline- and denudatine-type diterpenoid alkaloids and lays the groundwork for further studies toward their complete synthesis and the preparation of biosynthetically relevant derivatives.