Masters Thesis

Synthesis of macrocyclic ketone mimic of zampanolide

(−)-Zampanolide is a medicinally and structurally intriguing macrolide originated from marine sponges Fasciospongia rimosa and Cacospongia mycofijiensis. It exhibits nanomolar antiproliferative activity against both drug-sensitive and multidrug-resistant cancer cells. Nonetheless, the natural scarcity and the challenging total synthesis of zampanolide have restricted the supply for in vivo study. We envision that the lactone moiety of zampanolide is metabolically vulnerable in vivo which has been exemplified by Eribulin. Therefore, this thesis aims to synthesize a macrocyclic ketone mimic of zampanolide with a metabolically stable and synthetically simplified structure. Towards this end, two generations of total syntheses have been attempted. In the first-generation synthesis, the crucial carbon bridge C17-C-C1C2 has been constructed through a critical Grignard reaction. A key intermediate C13-C18 branched C17-C-C1-C8 (45) was achieved through 14-step transformation. However, the connection of fragment C9-C11 to 45 using Williamson ether synthesis was unsuccessful. We then turned to our second-generation synthesis and successfully constructed the ether linkage between fragment C13-C18 and fragment C9-C11 via Williamson ether synthesis. Fragment C9-C18 was incorporated into Fragment C1-C8 through a critical Grignard reaction. So far, we have achieved a highly advanced key intermediate C9-C18 branched C17-C-C1-C8 (53) via 15 linear steps synthesis (24 steps in total). Only two steps remained to accomplish the core structure of the zampanolide ketone mimic.

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