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dc.contributor.authorChen, Dezhi
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2017-08-31T17:30:07Z
dc.date.available2017-08-31T17:30:07Z
dc.identifier.urihttp://hdl.handle.net/1974/22633
dc.description.abstractThapsigargin 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.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectNatural Producten_US
dc.subjectTotal Synthesisen_US
dc.subjectThapsigarginen_US
dc.subjectSERCAen_US
dc.titleTotal Synthesis of Thapsigarginsen_US
dc.typeThesisen
dc.description.degreeDoctor of Philosophyen_US
dc.contributor.supervisorEvans, P. Andrew
dc.contributor.departmentChemistryen_US
dc.embargo.termsI want to restrict this thesis because it contains ongoing and unpublished results.en_US
dc.embargo.liftdate2022-08-30T17:05:01Z


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