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Open Access Publications from the University of California

Development of a Unified Strategy to the C18-, C19-, and C20-Diterpenoid Alkaloids

  • Author(s): Marth, Christopher James
  • Advisor(s): Sarpong, Richmond
  • et al.

Chapter 1 of this dissertation lays the foundation for understanding the role diterpenoid alkaloid natural products could play in the development of novel pharmaceuticals and probes for chemical biology applications. The chapter describes ethnomedical uses of Aconitum plants, the bioactivities of select diterpenoid alkaloids, and successful total syntheses of the diterpenoid alkaloids.

Chapter 2 details our ‘family-oriented’ strategy for developing a unified route to the C18-, C19-, and C20-diterpenoid alkaloids. By identifying the common fragments comprising the structural complexity of the diterpenoid alkaloids, we have been able to expedite our retrosynthetic analysis centered on a divergent strategy towards accessing members in each of the families.

Chapter 3 describes our efforts at employing the AE ring fragment for the synthesis of the diterpenoid alkaloids. Key to this strategy is the use of a meta-π-arene photocycloaddition reaction for directly constructing the [3.2.1] bicycle of the C18- and C19-diterpenoid alkaloids. Efforts toward accomplishing this objective are detailed herein along with an improved methylenation sequence of the hydrindanone core, a single-step lactone to lactam chemical transformation, and aryl addition attempts to AE bicycle containing substrates.

Chapter 4 focuses on our efforts at employing the AEF tricycle in the synthesis of the C18- and C19-diterpenoid alkaloids using cycloaddition strategies. Various meta-π-arene photocycloaddition precursors were synthesized, and a successful substrate was identified. The major differences between the successful and unsuccessful substrates are described in the chapter, as well as efforts towards employing alternative cycloaddition strategies for forging the targeted [3.2.1] bicycle.

Chapter 5 details our unified strategy to the diterpenoid alkaloids. Described in this chapter are the rearrangement of the C20-denudatine type [2.2.2] bicycle to the [3.2.1] bicycle of the C18 and C19 natural products, the use of the rearrangement in the synthesis of liljestrandinine (C19), and current work towards the synthesis of weisaconitine D (C18).

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