Total Synthesis of Thapsigargins
Thapsigargin is a complex, densely oxygenated guaianolide, which functions as a selective and irreversible subnanomolar inhibitor of sarco/endoplasmic reticulum Ca2+ ATPases. Importantly, a prodrug of this natural product, mipsagargin, is currently in late-stage clinical trials for the treatment of multiple cancers. Nevertheless, the limited availability of the material from natural sources, coupled with an estimated demand of one metric ton per annum, provides a compelling mandate to develop a practical total synthesis of this agent. This thesis describes the development of a concise, efficient and scalable total synthesis of thapsigargin and related natural products, and it is divided into four chapters. Chapter 1 provides an account of thapsigargin including its isolation, biosynthetic pathway, biological activity, and focuses on the previously reported strategies towards the synthesis of thapsigargin natural products. Chapter 2 describes our synthetic efforts towards the total synthesis of thapsigargin by using a rhodium-catalyzed [(3+2)+2] carbocyclization reaction as the key step. This strategy enabled the rapid construction of the highly functionalized guaianolide skeleton present in thapsigargin. Chapter 3 describes the successful route towards the total synthesis of thapsigargin by using an enantioselective ketone alkylation and a diastereoselective pinacol/lactonization cascade as the key steps. Our synthetic strategy is inspired by nature’s carbon−carbon bond formation sequence, which facilitates the construction of a highly functionalized guaianolide skeleton in five steps. Overall, the total synthesis of thapsigargin was accomplished in 12 steps and with 5.8% overall yield from the commercially available (R)-(−)-carvone. Chapter 4 discusses our ongoing work on the synthesis of other members of thapsigargin natural products, which is exemplified by the completion of the total synthesis of nortrilobolide in 10 steps and with 13.3% overall yield from the commercially available (R)-(−)-carvone. The divergent nature of our strategy should permit the rapid preparation of all the members of thapsigargins and a library of simplified thapsigargin analogs for detailed structure−activity relationship studies.