Design and Synthesis of Hybrid Peloruside a - Laulimalide Analogues

Abstract

The secondary metabolite peloruside A (+)-1, isolated from the New Zealand sponge Mycale hentscheli, has attracted much interest as a potential anti-cancer agent. Functioning by stabilising microtubules and stopping mitosis in the G2-M phase of the cell cycle, peloruside A has a mode of action similar to that of the successful billion dollar anticancer agent paclitaxel (Taxol). More recently, it has been shown that (+)-1 competes with laulimalide (-)-2 for binding to microtubules, suggesting the agents have the same, or at least overlapping, binding sites. Thus, a series of analogues (5a-f) have been designed which incorporate key features of both (+)-l and (-)-2. A retrosynthetic analysis of 5a-f breaks the molecules into two major fragments, C-1 to C-11 aldehydes and C-12 to C-24 methyl ketones. This thesis reports on the synthesis of each of these key fragments, as well as studies towards their coupling via 1,5-anti-selective aldol reactions. The C-1 to C-11 fragment is synthesised by two strategies. The first involves a hetero-Diels-Alder reaction to form the C-5 to C-9 pyran moiety. Problems attributed to the added steric bulk from the C-10 gem-dimethyl group are discussed. In the second, the same moiety is prepared via a ring-closing metathesis reaction. An efficient route to the C-12 to C-24 fragment is also discussed, using a ring-closing metathesis reaction as the key step. Studies, towards proposed coupling of the fragments via an aldol reaction invoking 1,5-anti selectivity are described, including model reactions which aid in determining the scope of the reaction and problems which resulted.