Synthetic studies towards the cytotoxic marine natural product diazonamide A
The thesis describes synthetic studies towards the marine natural product diazonamide A. This unprecedented compound was recently isolated from a colonial ascidian and displays exceptional levels of cytotoxic activity against human cancer cell lines. The Introduction includes an account of how diazonamide A was isolated and its structure determined. This is followed by a summary of the different natural products which have been isolated from ascidians, and highlights the structural similarities between these compounds and diazonamide A. The Introduction concludes with a review of structurally related natural products which concentrates on compounds containing oxazole rings or biaryl bonds. The Results and Discussion section of the thesis details our general strategy for a synthesis of the macrocyclic aromatic core of diazonamide A. A synthesis of the two key fragments in this strategy, namely the benzofuran oxazole unit and the iodoindole unit, is then described. This is followed by the elaboration of these units towards the target macrocycle. A detailed discussion is presented throughout this section including a review of the Heck and Ullmann reactions, and methods of oxazole formation. This section culminates by describing our initial synthetic efforts on an alternative approach to the macrocyclic core of diazonamide A. The third chapter of the thesis is the Experimental section containing full details of the preparative work completed and listing spectroscopic and analytical data for all new compounds synthesised during the study. The thesis is concluded by a schematic account of the contemporaneous work towards a total synthesis of diazonamide A that has been conducted by four other research groups.