Total Synthesis of Complex Indole Diterpenoid Natural Products: Shearilicine and Paspalicine
Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Newhouse, Timothy
Abstract
This dissertation describes the synthetic studies towards complex indole diterpenoids, which are centered around a versatile key bond disconnection between the indole C2 and the rest of the diterpenoid scaffolds. This biomimetic bond disconnection can potentially lead to various core motifs within this family of molecules. Through this strategy, we accomplished the first total synthesis of complex carbazole diterpenoid shearilicine and achieved significant progress towards paspalicine. Chapter one discusses the biological significances and structural features associated with the family of indole diterpenoids, which inspired our interest in synthesizing these molecules. Impactful previous synthetic achievements are presented to analyze their synthetic plannings, and the uniqueness of the approaches developed in our group is highlighted. In Chapter two, we report the first total synthesis of the complex carbazole indole diterpenoid shearilicine in a 11-step sequence. The rapid assembly of the scaffold was enabled by the difunctionalization on chiral building block (R)-carvone followed by Pd-mediated construction of the carbazole core. Chapter three presents our attempts to realize the central five-membered ring formation initiated from indole C2 position using three distinct mechanistic manifolds. We have identified a ligand-based reductive Heck reaction that can lead to both 5-exo and 6-endo products, and the six-membered ring formation can also be achieved via a radical pathway. Having addressed the challenges in confirming the relative stereochemistry of the 5-exo product, we verified that the reductive Heck reaction provided the undesired cis-diastereomer. Our ongoing endeavors to reverse the stereoselectivity will be discussed in this chapter. Detailed computational studies on the cationic cyclization will also be presented.
Recommended Citation
Zhu, Yingchuan, "Total Synthesis of Complex Indole Diterpenoid Natural Products: Shearilicine and Paspalicine" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1102.
https://elischolar.library.yale.edu/gsas_dissertations/1102
