Biomimetic Synthesis of Fused Polycyclic Ethers

本项目研究有毒赤潮现象中产生的稠合多环醚的仿生合成。虽然这些结构复杂的化合物的生物合成途径尚未完全阐明，稠合的多环醚结构被认为是由相对简单的无环多烯前体产生的多环氧化物化合物的区域选择性和立体特异性串联氧杂环化引起的。本项目将集中于模拟这些生物合成的氧杂环化反应，合成hemibrevetoxin B和一种新发现的五环天然产物brevenal。Brevenal是特别令人感兴趣的，因为它是其他稠合多环醚（如短吻蝮蛇毒素B）的神经毒性活性的无毒竞争性抑制剂。同位素标记的多烯对应的可能的生物遗传的前体的两种天然产物也将被合成。在合作工作中，这些多烯和衍生的多环氧化物将在饲养实验中与培养的Karenia brevis，生物体负责赤潮和相关的生产稠合多环醚天然产物毒素的研究。埃默里大学化学系的麦克唐纳说。麦克唐纳教授和他的学生正在探索“赤潮”现象产生的毒素的合成，这种现象导致美国东南部大西洋和墨西哥湾沿岸沿着的鱼类死亡，并在人类摄入受污染的鱼类时产生神经中毒症状。他们的合成旨在模仿自然界使用的合成路线，包括对新发现的天然产物Brevenal的研究，Brevenal是一种无毒的竞争性抑制剂，可抑制其他赤潮毒素的神经毒性活性。麦克唐纳教授的研究将揭示负责复杂毒素的生物合成的基本过程。此外，他们承诺的影响，在开发潜在的治疗赤潮毒性，价值的情况下，由于气溶胶形成的自然波作用，以及故意交付的赤潮毒素。

This project addresses the biomimetic syntheses of fused polycyclic ethers produced in toxic "red tide" phenomena. Although biosynthetic pathways for these structurally complex compounds have not been completely elucidated, fused polycyclic ether structures are presumed to arise from regioselective and stereospecific tandem oxacyclizations of polyepoxide compounds arising from relatively simple acyclic polyene precursors. This project will focus on mimicking these biosynthetic oxacyclizations in the synthesis of hemibrevetoxin B and a newly discovered pentacyclic natural product, brevenal. Brevenal is of particular interest, as it is a nontoxic, competitive inhibitor for the neurotoxic activity of other fused polycyclic ethers such as brevetoxin B. Isotopically labelled polyenes corresponding to the possible biogenetic precursors of both natural products will also be synthesized. In collaborative work, these polyenes and derived polyepoxides will be studied in feeding experiments with cultures of Karenia brevis, the organism responsible for the red tide and associated production of fused polycyclic ether natural product toxins.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Frank E. McDonald of the Department of Chemistry at Emory University. Professor McDonald and his students are exploring the synthesis of toxins produced in "red tide" phenomena, responsible for fish kills along the Atlantic and Gulf Coast areas of the southeastern United States and producing neurotoxic symptoms in humans when contaminated fish are ingested. Their syntheses are designed to mimic the synthetic routes used by Nature, and include studies of a newly discovered natural product, brevenal, which serves as a nontoxic, competitive inhibitor for the neurotoxic activity of other red tide toxins. Professor McDonald's studies will shed light on the fundamental processes responsible for the biological synthesis of complex toxins. In addition, they promise impacts in the development of potential treatments for red tide toxicity, of value in the case of toxicity due to aerosol formation by natural wave action as well as intentional delivery of red tide toxins.