Chemistry Defense: Hyejin Lee- Total Synthesis and Biological Evaluation of 4α,9α,10α-Trihydroxyguaia-11(13)en-12,6α-olide

Total Synthesis and Biological Evaluation of 4α,9α,10α-Trihydroxyguaia-11(13)en-12,6α-olide Natural products remain central to therapeutic discovery, with nearly two-thirds of approved small-molecule drugs derived from or inspired by natural scaffolds. Beyond drug discovery, they have served as valuable chemical probes, enabling the mapping of biological pathways with precision. Their evolutionary refinement often confers remarkable target selectivity, making them both excellent drug leads and indispensable research tools. Among bioactive motifs, the α-exo-methylene-γ-butyrolactone (AMGBL) unit is especially notable as an electrophilic handle, frequently associated with potent anticancer activity. This dissertation reports the total synthesis and biological evaluation of 4α,9α,10α-trihydroxyguaia-11(13)en-12,6α-olide (1), a guaianolide-type sesquiterpene lactone containing an AMGBL moiety. Originally isolated from Anvillea garcinii, compound 1 was reported to possess potent antifungal activity. Inspired by its translational potential, total synthesis of compound 1 was pursued to provide a reliable and efficient route enabling access to derivatives and chemical probes. A modular synthetic strategy was adopted to assemble the guaianolide 5,7,5-tricyclic core to enable downstream structure-activity relationship studies, with two complementary routes that differed in the stage of tertiary hydroxyl installation. Ultimately, completion of the synthesis provided access to compound 1 and allowed assignment of its absolute configuration by X-ray crystallography of a key intermediate. Biological studies revealed that synthetic 1 lacked antifungal activity against Candida albicans. However, high-throughput screening using Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) platform revealed promising anticancer activities, including potent inhibition of BT12 atypical teratoid/rhabdoid tumor cells and broader activity across multiple cancer models. Together, these studies present a robust route to the guaianolide scaffold, establish its previously unassigned absolute stereochemistry, and reveal the anticancer activity of 1. The results identify this scaffold as a promising entry point for the development of ATRT-directed therapeutics and provide a foundation for future structure-activity and mechanistic investigations.