Biomimetic Synthesis of Fused Polycyclic Ethers

Emory University, Atlanta GA

Investigators

Abstract

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.