Abstract:
In recent years numerous tubulin ligands with antimitotic properties have been discovered. The first ligand found to stabilise microtubules (polymerised tubulin), paclitaxel (Taxol®), has been successfully used for the clinical treatment of solid tumours for over two decades. However, several characteristics of the drug make it a less than ideal chemotherapeutic treatment, making the search for new microtubule stabilising agents with increased efficacy and fewer side-effects all the more pertinant. A recent addition to the family of microtubule stabilizing agents is peloruside A (1), a 16-membered macrolide isolated from the New Zealand marine sponge Mycale hentscheli. Peloruside A displays potent antimitotic activity, however the combination of its inherent structural complexity and the difficulties in isolating sufficient quantities of the macrolide from natural sources, has lead to much interest in it's synthesis. Total synthesis also allows for the development of structurally modified compounds (analogues) of peloruside A, which in turn will lead to structure-activity studies and the potential to discover an even more potent microtubule stabilising agent.
The retrosynthetic analysis of peloruside A reveals four key segments: The C- 1 to C-2 fragment, the C-3 to C-7 segment, the C-8 to C-11 segment and the C-12 to C-24 portion. This thesis presents studies towards the synthesis of the C-1 to C-11 portion of peloruside A, methodology for the incorporation of structural modifications at the C-2 and C-10 sites of peloruside A and studies towards the synthesis of the C-1 to C-11 portion of another member of the peloruside family - peloruside C.
Efficient syntheses of two C-10 modified analogues (with diethyl and cyclobutyl groups in place of the gem-dimethyl group) were developed using a Claisen-like condensation to establish the carbon framework and install the C-10 modification. Eight differentially protected C-3 to C-7 segments were also prepared, using a boron-mediated asymmetric, allylation to create the stereocentre, at C-5, as this facilitates in the flexibility of the overall total synthesis. One of these segments was further elaborated in excellent yields and selectivity to the C-1 to C-7 segment via a boron-mediated 1,2-synaldol reaction. Methodology was also explored for the synthesis of C-2 modified, C-1 to C-7 segments and most noteworthy, the synthesis of a C-2 methyl analogue of the C-1 to C-7 segment was completed.
While attempts to elaborate these segments to the C-1 to C-11 portion of peloruside A (and analogues thereof) were unsuccessful, it was found that the overall strategy could be adapted to synthesise other members of the peloruside family. Significant progress towards the synthesis of the C-1 to C-11 portion of peloruside C was achieved. Here, two differentially protected C-3 to C-11 segments and the protected C-1 to C-7 segment of peloruside C were successfully synthesized.
