The chivosazoles, isolated in 1994 from the myxobacterium Sorangium cellulosum by Höfle and co-workers, are a family of polyketides that exhibit a range of potent biological activity including antifungal and cytoxicity against human cancer cell lines. This thesis details studies towards the total synthesis of the chivosazoles. Chapter 1 discusses the isolation, characterisation and biological activity of these compounds, as well as the first total synthesis of chivosazole F (12) by the Kalesse group. Chapter 2 describes the development of a highly convergent approach to assemble the chivosazoles from three key fragments A (69), B (70) and C (71), of similar size and complexity. A flexible endgame coupling of these fragments is proposed via a Stille- Suzuki-macrolactonisation or Stille-esterification-Suzuki sequence. The first generation route to access fragment A is described, utilising Paterson 1,4-syn boron aldol methodology and an Evans-Tishchenko 1,3-anti reduction to define the stereochemistry. The relative configuration of this subunit, as proposed by Kalesse, was independently confirmed by synthesis of C28-C35 degradation fragment 21. The C19-C22 stereotriad featured in fragment B was installed, again, using a boron-mediated aldol reaction followed by an Evans-Tishchenko reduction. The required oxazole moiety was formed via a Williams-Wipf cyclisation procedure. Having prepared fragments A and B, coupling conditions were established to form the northern hemisphere subunit and the NMR data of this region correlated favourably with that of the natural product. Chapter 3 describes the second-generation route to fragment A (69), featuring fewer steps and improved scalability for preparation of multi-gram quantities of this material. Different strategies for modification of the functional group at C16 on the oxazole ring for planned coupling with fragment C (71) were explored. Unexpected difficulties with the installation of this coupling handle are outlined, as well as a modification to our oxazole-formation strategy to overcome these challenges. As an alternative to eventual esterification or macrolactonisation at C1, Still-Genarri and Ando olefinations were investigated on model systems for formation of the C2-C3 (Z)-olefin. Advanced C7-C35 fragments are constructed via subsequent Stille cross-couplings in preparation for formation of the macrolactone core of the chivosazoles. Chapter 4 outlines three potential highly-convergent endgame strategies for ongoing studies. The experimental procedures and spectroscopic characterisation of the compounds discussed are found in Chapter 5 and the Appendix.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:545410 |
| Date | January 2011 |
| Creators | Gibson, Lisa |
| Contributors | Paterson, Ian |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/241106 |
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