Convergent synthesis of Bryostatins

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Compounds isolated from natural sources, for example plants, have provided very important leads over the years for the discovery of drugs and pharmaceuticals. Recently, many very complicated compounds have been isolated from microorganisms in the sea and found to possess anti-cancer activity. One such group of compounds are the bryostatins. These display potent biological activity and are being tested for clinical use in many trials worldwide. The problem is that access to the bryostatins is very difficult. Aquaculture techniques are providing a few hundred grammes a year of one of the bryostatins, but this supply is not meeting demand and, in particular, is not providing enough material for the chemical modifications necessary for a study of the influence of structure on biological activity. To date, three syntheses of bryostatins have been reported, two from the USA and one from Japan. These are outstanding examples of modern and sophisticated chemical synthesis but because of their length cannot contribute significantly to the supply of bryostatins or analogues for biological studies.It is intended to develop a shorter synthesis of bryostatins which will provide access to synthetic analogues for studies of the effect of structure on biological activity. Initially a naturally occurring bryostatin will be prepared to develop the methodology but this should open the way for the preparation of analogues. The longer term objective, albeit outside the scope of this application, is to prepare a simpler analogue with improved biological activity and reduced toxicityHowever, this is a very ambitious programme and synthetic organic chemistry at this level is very difficult to carry out. The present application is for support for an experienced research worker to continue our studies in this area for twelve months. During this time it is intended to finalise our synthetic strategy, to prepare close analogues of the bryostatins, and hopefully prepare a natural bryostatin, so establishing the viability of our approach.