Steps Toward The Total Synthesis of The Chrysosporazine Family

Cancer is one of the leading causes of death worldwide, with 19.3 million new cancer cases and 10 million deaths in 2020 alone. In the United States, cancer was the second leading cause of death after heart disease. One of the reasons that cancer is so frequently terminal is that cancerous cells frequently develop multidrug resistance (MDR) to frontline chemotherapeutical treatments, resulting in cancers cannot be treated and are inevitably fatal. This makes the discovery of ways to combat MDR so important in the treatment of cancer. The chrysosporazines are a family of recently discovered (2019) natural products that have demonstrated promising in vitro activities in reversing drug resistance of colon cancer cell lines. To date, there is currently no reported total synthesis for this family, thus limiting future studies. Since the current method of acquiring members of the chrysosporazine family involves harvesting them in milligram quantities, it is crucial that there is an effective synthetic route to create more material for full exploration of the properties of this alkaloid family. This thesis consists of the first total synthetic route towards chrysosporazine D following a convergent strategy using a palladium-catalyzed cyclization to generate the piperazine core motif. This route will be used in the synthesis of the remaining chrysosporazines, as the piperazine core is evident in the entire family. Ongoing research is focusing on optimizing the final steps of the synthesis of chrysosporazine D to yield the first synthesis of a member of this anticancer alkaloid natural product family