| (+)-Peloruside A was first isolated by Northcote and coworkers in 2000 from the marine sponge, Mycale hentscheli collected from Pelorus Sound on the South Island of New Zealand.1 In mammalian cell lines, (+)-peloruside A is an inhibitor of cell proliferation with an IC50 in the low nanomolar range (4-15 nM). (+)-Peloruside A was also shown to induce apoptosis in a dose-dependent manner in murine (32D) and human myeloid cell lines (HL-60).2; This dissertation has been divided into four chapters that have several components each. Chapter 1 provides a detailed background for (+)-peloruside A that begins by walking the reader through the originally-reported spectroscopic assignments. Then, since it is often the case that a synthetic, organic chemist refers to the biological activity of a molecule without really having an appreciation for what it means, a brief foray into the biological realm has been made. With this risky endeavor, it was my sole intent to frame a context for microtubule stabilizing agents like (+)-peloruside A; it is my hope that this effort serves the synthetic reader well and does not bore the biology pundits. Lastly, a comprehensive survey on the previous synthetic work that has been published as of July, 2005 on peloruside A has been included.; Chapter 2 describes the work that I have done, largely as an ongoing side-project, to advance No-Deuterium (No-D) Proton NMR spectroscopy. The two major sections in this chapter discuss the general procedure for taking No-D spectra and how No-D NMR has been used to determine the concentrations of commonly-used reagents that are otherwise difficult to assess.; Chapter 3 reports the progress toward the C12-C20 segment of (+)-peloruside A. An efficient route to an intermediate only several steps short (specifically, a reduction, two protections and a hydrolysis) of the desired C 12-C20 segment has been established.; Chapter 4 constitutes the bulk of my effort and spans my full graduate tenure. This chapter describes my efforts toward the synthesis of the enantiopure C1-C9 fragment of (+)-peloruside A. What will become apparent early on is the underlying theme of my synthetic efforts---the exploitation of symmetry.; 1"Peloruside a: a potent cytotoxic macrolide isolated from the New Zealand marine sponge Mycale sp." West, L. M.; Northcote, P. T.; Battershill, C. N. J Org. Chem. 2000, 65, 445-9. 2"Induction of apoptosis by the marine sponge (Mycale) metabolites, mycalamide A and pateamine." Hood, K. A.; West, L. M.; Northcote, P. T.; Berridge, M. V.; Miller, J. H. Apoptosis. 2001, 6, 207-219. |
