The broad objectives of our laboratory are four fold. (i) We seek to develop new strategies and new reaction modalities of value to organic synthesis. Enhancements in synthesis are, per se, of value to society since synthesis lies at the core of advances in the pharmaceutical, animal health and agricultural industries. (ii) We seek to direct these findings to achieve academic level total syntheses of natural products of significant structural complexity and promising biological profiles. In HL 25848-22-26 we focus on natural products of relevance to biological signaling, DNA replication and inflammation. (iii) While we emphasize completion of an academic level synthesis, where the situation is appropriate, we fine tune the synthesis with a view to optimization and possibly to scale up. (iv) Finally, we use our chemistry to help elucidate SAR profiles and with suitable collaborations, to deal with issues of mechanism. Our proposal is broadly divided into two components. The major thrust is toward a group of five new natural product objectives. Here, but for a few background experiments which will be described, we are starting essentially from the beginning. The first two total synthesis targets are phomactin A (1) and xestocyclamine (2). Phomactin A is a PAF antagonist and xestocyclamine is a highly active PKC inhibitor. While these structures are totally different from one another, we hope to use them to illustrate the emerging power of the B-alkyl Suzuki reaction in organic synthesis, particularly as a device for stereospecific macrocyclization. We hope to use this reaction to construct the ansa like bridges of both phomactin A and xestocyclamine. Another orienting target is guanacastepene (3), which is apparently active against vancomycin resistant bacteria. Along the way of its proposed synthesis we will undoubtedly learn much about the SAR profile of guanacastepene. While it's too early to conjecture on a mechanism of action we will certainly be seeking collaborations to deal with this problem. Moreover, the molecule provides opportunities for advances in synthetic strategy as well as key methodological advances (for instance, hydrazulene synthesis, bond reorganization reactions, activated cyclopropanes and oxidative furan disconnections. We then discuss the target alkaloid metabolite phalarine (4). The synthesis of this compound will occasion us to probe frontier issues in indole chemistry and more broadly carbon-carbon bond formation by cross coupling of complex systems. Still another target is cribrostatin IV (5). This compound is related to ecteinascidin 743 (6). A formal total synthesis of ET 743 is well advanced in our laboratory. While the mechanism of action of ET 743 has been suggested to involve inhibition of transcriptional activation, the mode of cytotoxicity of cybrostatin is unknown. Indeed, it will be of great interest to compare the mode of action of cribrostatin and ET 743. For this purpose we must achieve the synthesis of cribrostatin since it is currently available only with the greatest of difficulty from coral sources. In addition, we hope to complete the total synthesis of gelsemine (7), as well as ET 743 itself. Projects 6 and 7 have reached the point where our general route is clear. However, several significant issues and learning opportunities remain.
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