FUNGICIDAL AND NEUROTOXIC MARINE NATURAL PRODUCTS

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The marine environment continues to provide us with a wide variety of biologically and architecturally interesting natural products. Unfortunately, we are unable to isolate sufficient quantities of many of these bioactive compounds for their full evaluation. Outlined herein are our plans to improve the status quo through the synthesis of bioactive marine toxins and the development of new and improve (more efficient synthetic techniques. The synthesis of the bioactive marine natural products that are described in this proposal will not only provide quantities of materials that are not currently available but it is only through these efforts that a true understanding of the properties of these molecules will become available. We are drawn to two targets. One of these, pinnatoxin A, is a potent neurotoxin though to be responsible for seasonal outbreaks of food poisoning from the ingestion of shellfish throughout Asia. The other, gambieric acid A, is among the most potent antimicrobial agents known to man. Both of these, as well as other similar species, are believed to come from dinoflagellates are probably at least partially responsible for red tide catastrophes. Our synthesis of pinnatoxin A will include many novel transformations including free-radical approaches to spiro-fused rings, macrocylic rings and bis-ketal rings as well as free-radical coupling reactions which utilize silicon as a stereo-and regio-controlling feature. We anticipate that these studies will have implications far beyond the synthesis of pinnatoxin A. We intend to answer several important questions during the synthesis of gambieric acid A. First, can an iterative strategy employing enol ether epoxidation and ring closing metathesis be used to generated fused ethers of various ring sizes as are present in the marine "ladder toxins"? Also, is this strategy amenable to its use on a solid support? Once this last goal has been achieved, it is conceivable that libraries of pharmacologically relevant fused cyclic ethers could become available. In addition to their synthesis through our iterative strategy, we are also interested in the biosynthesis of fused cyclic ethers and plan to explore polyepoxide cyclizations towards their synthesis.