The Synthesis of New Analogues of the Natural Product Th：天然产物的新的类似物的合成.docx

The Synthesis of New Analogues of the Natural Product ThapsigarginMalcolm TaitSeptember 2006This dissertation is submitted for the degree of Master of PhilosophyBP Whiffen LaboratoryDepartment of ChemistryUniversity of CambridgeEmmanuelCollegeLensfield RoadSt Andrews StreetCambridgeCambridgeCB2 1EW CB2 3APDeclarationThis dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration, except where specifically indicated in the text. The document does not exceed the word limit of 15,000 words (exclusive of tables, footnotes, bibliography and appendices), as set by the Degree Committee for the Faculty of Physics and Chemistry.Malcolm TaitSeptember 2006AbstractThis thesis describes the synthesis of new analogues of the natural product thapsigargin, a potent inhibitor of the Sarco- Endoplasmic Reticulum ATPase (SERCA).The first section provides an introduction to the chemistry and biology of thapsigargin and its analogues. The structural elucidation of the natural product and selective manipulations of the peripheral functionality is described. This is followed by a detailed account ofthe known structure-activity relationshipfor analogues derived from these manipulations, and the development of a particular compound (L12ADT) as a potential treatment for prostate cancervia a prodrug strategy. The recently completed total synthesis of thapsigargin and an analogue program initiated in the Ley group are also reviewed.The second part of this thesis describes the work carried out as part of this project and is split into two sections. The first section discusses studies toward symmetrically simplified meso analogues of thapsigargin, from which a potential new piece of methodology has been established involving the [3+2]-cycloaddition of silyl enol ethers with oxy-allyl cations. The second sectiondescribes the synthesis of an alternative analogue derived from an intermediate in the natural product synthesis. Th