Towards the Synthesis of Hybrid Peloruside A and Laulimalide Analogues

Abstract

(+)-Peloruside A is a novel cytotoxic marine natural product isolated from the New Zealand sponge Mycale hentscheli(42). Peloruside A is a potential anticancer agent that has a similar mode of action to that of the successful drug paclitaxel. Biological analysis indicated that (+)-peloruside A promotes tubulin hyperassembly and cellular microtubule stabilisation which lead to mitosis blockage in the G2/M phase of the cell cycle and consequent cell apoptosis(43),(47). (-)-Laulimalide is also a cytotoxic natural product with microtubule stabilising bioactivity, and is a potential anticancer agent(47). Biological analysis showed that (+)-peloruside A and (-)-laulimalide are competitive, suggesting that they bind to the same active site(47). (+)-Peloruside A and (-)-laulimalide also display synergy with taxoids(47). Due to the structural complexity of peloruside A, our research has focused on developing an analogue 151 for ease of synthesis. Thus, the simplified C5-C9 dihydropyran moiety of (-)-laulimalide, with fewer stereocentres than that of (+)-peloruside A, has been incorporated into analogue 151 whilst retaining the 16- membered ring backbone of (+)-peloruside A. The proposed synthesis of 151 involves a Yamaguchi macrolactonization, a 1,5-anti-aldol coupling, and a ring closing metathesis as key reactions. This thesis reports on the synthesis of key fragments of analogue 151 and the crucial 1,5-anti-aldol coupling reaction for the assembly of the carbon backbone.