Exploiting the Maitland-Japp Reaction. A Highly Convergent Total Synthesis of Phorboxazole A.

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With 156,000 people dying each year in the UK because of cancer, the government announced in 1999, a major initiative highlighting cancer treatment as an area of high national priority. In support of this initiative they have invested an extra 210M in the battle against cancer, with an additional 20M a year specifically targeted for research. One of the more successful strategies for cancer treatment is the development of new chemotherapeutic agents. Over the last few years some of the most successful and promising agents have been natural products isolated from marine organisms. One of the most promising lead compound is phorboxazole A. Its potent cytostatic activity assessed as G150 <1.6 nM against an entire panel of human cancer cell lines, its as yet undetermined mode of action, its unprecedented structural features and its scarcity of supply combine to make phorboxazole A a priority target for a total synthesis which can yield gram quantities of the material. A total synthesis which can deliver this would be of considerable importance to the pharmaceutical industry.Our synthetic strategy is a modular one exploiting our recent renaissance of the Maitland-Japp and the related decarboxylative Maitland-Japp (DMJ) and acylative Maitland-Japp (AMJ) reactions for the formation of the functionalised tetrahydropyrans (THP) rings present in 1. The pot, atom and step economic nature of these reactions will enable the efficient synthesis of suitably functionalised tetrahydropyran units which will be coupled to form the natural product. The inherently modular nature of this route will allow a great deal of latitude in selecting the appropriate functionality required for coupling. In addition, it will also allow for the expedient synthesis of analogues of 1. This work is timely, challenging and adventurous making it appropriate for EPSRC funding. However, if successful it will lead to a shorter, more efficient and versatile route, which can generate gram quantities of this important molecule. We therefore seek EPRSC funding for manpower and consumables to carry out the synthesis of phorboxazole A.