UC Irvine

The research described herein focuses on the development of synthetic strategies to facilitate the understanding of the lissoclimide’s biological activity and the development of a general synthetic route towards C20-diterpenoid alkaloids. Chapter 1 focuses on the isolation, biological activity, and previous efforts towards the lissoclimide natural products. Previous syntheses by the Vanderwal lab and collaborative work with the groups of Yusupov, Blanchard, Furche, and Horne are also described.Chapter 2 focuses on the syntheses and biological evaluation of the lissoclimide analogues. This chapter describes the optimization efforts of the Evans aldol sequence to reliably synthesize all the desired C2 halogen-bearing lissoclimides and efforts to develop a stereoselective methylation strategy at the C2 position of sclareolide. It concludes by analyzing the biological activity of these analogues against multiple cancer cell lines and the X-ray cocrystal structures of these analogues bound to the 80s eukaryotic ribosome. Chapter 3 marks the transition towards our investigation into the syntheses of diterpenoid alkaloids. It focuses on the isolation, biological activity, and previous total syntheses of hetisine and hetidine-type diterpenoid alkaloids. Chapter 4 describes our work on developing an efficient and general route towards hetidine-type natural products. This chapter details different strategies employed to form the oxetane-bearing AB core, which would install C19 oxygenation and further diversify the core into several C20-diterpenoid alkaloids. Chapter 5 describes the successful synthesis of the carbon framework of hetidane and hetisine-type diterpenoid alkaloids. This expedient route utilizes a key MHAT bicyclization strategy to form the AB core as well as an intramolecular Diels Alder reaction to form the bicyclo[2.2.2]nonane adduct. It concludes with efforts to form the G ring and future work towards the synthesis of C20-diterpenoid alkaloids.