Investigations of Marine and Terrestrial Natural Products

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This research program explores both the synthesis of novel molecules and methodology studies. These novel natural products include gliovirin, ceanothine D, and the marinopyrroles. The methodology studies will involve mechanistic studies and further applications of the trisubstituted aziridine ring opening reactions. Gliovirin is known for its biological activity but it has never been synthesized. The proposed synthetic strategy will explore a furan Diels-Alder reaction that could prove applicable to other structurally similar compounds. Ceanothine D is a unique cyclopeptide alkaloid whose absolute configuration remains unknown. Two approaches are designed to synthesize this compound. The first will investigate a novel strategy using the aziridine opening methodology previously developed. The second approach will involve a more traditional synthetic strategy. The absolute configuration of the product will be established as well. Investigation of the trisubstituted aziridine ring opening reactions will continue. The reaction has shown utility in the stereoselective synthesis of quaternary centers. Application of different nucleophiles to these aziridines will elucidate the reaction mechanism and afford chiral synthons for other synthetic endeavors. The marinopyrroles are a class of densely halogenated natural products. These antimicrobial active bis-pyrrole structures exhibit axial chirality and tetrachlorination of the bis-pyrrole core. The proposed program will develop synthetic strategies for these novel natural products, expand current methodological studies, and work to educate students for the continued advancement of organic synthesis. With the support of this award from the Chemical Synthesis Program, Professor Madeleine Joullié of the Department of Chemistry at the University of Pennsylvania is exploring the synthesis and properties of molecules that exhibit promising biological activity. Efficient and reliable methods for their synthesis will enable the scientific community to understand the bioactivity of related natural or synthetic products. These bioactive molecules could provide new leads for anticancer and antibiotic drug discovery, influencing the fields of biology, chemistry and pharmacology. Gliovirin, a novel compound, presents a challenging target for synthesis and possesses significant bioactivity. A total synthesis of this natural product will establish reliable reactions to construct complex molecular structures as well as provide material for further biological evaluation. Ceanothine D was isolated from a flowering member of the Buckthorn family indigenous to eastern and central North America. The leaves from the plant were used as a substitute for tea during the Civil War and the brew was reputed to have hypotensive action. The medicinal use of the plant warrants an investigation into the chemicals responsible for its therapeutic effects. Its historical background and potential biological activity makes ceanothine D an interesting target. The marinopyrroles are antimicrobial structures that represent challenging synthetic targets and show a novel biological mechanism in the treatment of MRSA (drug-resistant staph infection), a clinically and sociologically relevant disease state. Scientific education of students and the general population is important to the future of society. Basic chemical research provides a platform for scientific education. The proposed program provides a fertile ground for basic research leading to advanced research areas. The proposed areas of interest will provide knowledge from which new scientific breakthroughs may occur. More importantly, the proposed studies will contribute to the education and future of many students including women and minorities, who have benefited from previous NSF Awards.