FUNGICIDAL AND NEUROTOXIC MARINE NATURAL PRODUCTS

海洋环境继续为我们提供各种各样的 具有生物学和建筑学价值的天然产品。 不幸的是，我们无法分离出足够数量的许多 对这些生物活性化合物进行充分的评估。这里概述的是 我们计划通过合成生物活性物质来改善现状 海洋毒素的开发和新的改进(更高效 合成技术。具有生物活性的海洋天然产物的合成 本计划书中描述的产品不仅将提供 当前不可用的材料数量，但仅限于 通过这些努力，才能真正了解这些 分子将变得可用。 我们被两个目标所吸引。其中一种，品纳毒素A，是一种有效的 尽管神经毒素是季节性食物暴发的原因 亚洲各地因摄取贝类而中毒。另一种， 冈比亚酸A是已知的最有效的抗菌剂之一 天哪。这两个物种，以及其他类似的物种，都被认为来自 可能至少对红色负有部分责任 潮汐灾难。我们合成的平纳曲霉毒素A将包括许多新的 包括螺环稠环的自由基方法在内的变换， 大环环、双酮环及自由基偶联 利用硅作为立体声和区域控制特征的反应。 我们预计，这些研究的影响将远远超出 平纳曲霉毒素A的合成 我们打算在合成过程中回答几个重要的问题 冈比亚酸A。首先，使用烯醇醚的迭代策略 用环氧化和开环复分解反应合成稠醚 海洋“阶梯毒素”中存在的各种环的大小？另外， 这一战略是否适合在坚实的支撑点上使用？这是最后一次 目标已经实现，可以想象，图书馆的 药理上相关的稠合环醚可能会出现。在……里面 除了通过我们的迭代策略合成它们之外，我们还 对稠合环醚的生物合成感兴趣并计划探索 聚环氧基醚的环化反应。

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.