Convergent syntheses of bryostatins

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Over the years, many compounds, natural products, have been isolated from plants, animals and other forms of life, e.g. micro-organisms. Some of these are very toxic but others have proved to be useful leads for the discovery of new pharmaceuticals, e.g. antibiotics such as the penicillins and cephalosporins, and taxol which has emerged for the treatment of certain cancers. About 20 years ago, a new group of very complex natural products, the bryostatins, was isolated from a marine animal, Buluga neritina, a bryozoan filter feeder, although more recently it has emerged that these compounds are actually produced by a micro-organism which cohabits with the bryozoan. The bryostatins were immediately recognized as having potent anti-cancer activity and have been of considerable interest to medicinal and synthetic chemists since. Although some side effects are observed when patients are treated with bryostatins, there are marked improvements when the bryostatins are prescribed in combination with other chemotherapies. The bryostatins have also been found to have many other potentially useful biological activities such as stimulation of the immune system, reversal of damage due to a stroke and memory enhancement in animal models. The actual modes of action of the bryostatins are partly understood although more remains to be done in this area.Notwithstanding these exciting biological activities, there are severe problems in the supply of bryostatins. To date they have been isolated from the natural marine source, but this is environmentally unacceptable and also very unreliable, for example, an aquaculture programme for the production of bryostatins has recently been discontinued. The bryostatins have been synthesized by organic chemists, but the early syntheses were very long and were not convergent, and so did not add to the supply of bryostatins for biological evaluation. More recently bryostatin like compounds have been designed. Some of these possess the activities of the natural bryostatins and are under clinical evaluation.The objectives of the present work are to develop a new and more convergent synthesis of bryostatins which can be used to provide material for biological evaluation. Initially the work will target a sub-group of bryostatins which has not been prepared before. Once the chemistry to achieve this objective has been sorted out, it will be applied to complete syntheses of other bryostatins and simpler analogues for biological evaluation.The synthesis which it is proposed to carry out has been studied for many years. It is hoped to complete the synthesis of a naturally occurring bryostatin in about thirty linear, i.e. sequential, steps. To date the first twenty six of these have been carried out successfully. It remains to find reagents and conditions for the final four steps and then to complete syntheses of naturally occurring bryostatins and analogues.