TOTAL SYNTHESIS OF THE ANTILEUKEMIC AGENT BRYOSTATIN 1

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Although still largely untapped, the oceans have proven to be a source of several families of marine natural products possessing potentially useful pharmaceutical properties. For instance, several compounds isolated from Bugula neritina have shown promise in certain anticancer tests, and bryostatin 1, a representative member of this group, indeed extends the average lifetime of leukemic mice by 52-59%. This project is specifically aimed at the synthesis of bryostatin 1, C47H68O17, a 26-membered macrolide with 11 chiral centers comprising a series of 1,2-and 1,3-diol moieties, pyran rings, and olefinic linkages. The compound is retrosynthetically dissected into three major fragments, which will be assembled in the final stages of the proposed synthesis. Therefore, the entire scheme is highly convergent thus rendering the actual execution of the synthesis practical, despite the structural complexity of the target molecule. All of the structural units embedded in bryostatin 1 can be constructed through several methodologies developed recently in our or other laboratories. Stereochemical problems to be encountered during the course of the synthesis will be resolved with the proper application of the concept now termed multiple asymmetric induction. The importance of this concept in acyclic stereochemical control has now been fully recognized. The pursuit of this project will undoubtedly enhance our synthetic expertise and further help identify new fundamental problems yet to be investigated in the field of organic synthesis. Of primary benefit, however, would be the wealth of information which could answer many questions concerning the structure/activity relationship of bryostatin. It is definitely intended to submit adequate samples of this marine product and its derivative for biological screenings.