Synthesis of Daucane-Type Sesquiterpenoids

Yiquan Zhao, Ph.D. Candidate Jiyong Hong Ph.D., Advisor Abstract: Human pancreatic cancer persists as a significant global health challenge with high mortality rates, and the precise etiology of pancreatic cancer remains elusive. While current treatments include surgery and conventional chemotherapeutic agents, the antiausterity strategy has emerged as a promising approach to target the tolerance of pancreatic cancer cells to nutrient-deprived microenvironments. In 2020, three natural products, namely ferutinin (1), a new daucane-type sesquiterpenoid (2) and kuhistanicaol G (3), were proved possessing potent antiausterity activity against PANC-1 human pancreatic cancer cells. However, their structure-activity relationships (SAR) and mechanism of action have yet to be elucidated. Therefore, we sought to establish an efficient and divergent route to complete the total synthesis of these natural products and to prepare analogs to probe SAR. This dissertation first describes the construction of two structural features of all three target compounds: a quaternary carbon center and a 5,7-fused bicyclic system with trans ring junction. The synthesis of 1 was subsequently accomplished following a few functionalizations. Additionally, this work includes preparation of the key allylic alcohol precursor to 2 and 3. Evaluations of the antiausterity activity of compounds 1 and 3, as well as four derivatives, are currently in progress. These synthetic efforts and establishment of SAR will aid in the development of chemotherapeutic agents with new mechanisms of action against human pancreatic cancer, offering hope for improved treatment outcomes.