Investigations of Marine and Terrestrial Natural Products

这个研究项目探索了新分子的合成和方法论研究。这些新的天然产物包括胶质瘤病毒、海洋肽D和海洋吡咯。方法学研究将包括三取代叠氮啶开环反应的机理研究和进一步应用。Gliovirin以其生物活性而闻名，但从未被合成过。提出的合成策略将探索呋喃Diels-Alder反应，可以证明适用于其他结构类似的化合物。海鞘氨酸D是一种独特的环肽生物碱，其绝对构型尚不清楚。设计了两种方法来合成这种化合物。第一个将研究一种使用先前开发的氮化吡啶开放方法的新策略。第二种方法将涉及一种更为传统的综合战略。产品的绝对构型也将建立起来。对三取代叠氮啶开环反应的研究将继续进行。该反应在立体选择性合成四元中心方面具有实用价值。将不同的亲核试剂应用于这些叠氮嘧啶，将阐明反应机理，并为其他合成工作提供手性合成物。海洋吡咯是一类密集卤化的天然产物。这些抗菌活性双吡咯结构表现出轴向手性和双吡咯核心的四氯化。该计划将开发这些新型天然产物的合成策略，扩展当前的方法研究，并努力教育学生继续推进有机合成。在化学合成项目的支持下，宾夕法尼亚大学化学系的Madeleine joulli<e:1>教授正在探索具有生物活性的分子的合成和性质。高效可靠的合成方法将使科学界能够了解相关天然或合成产品的生物活性。这些生物活性分子可以为抗癌和抗生素药物的发现提供新的线索，影响生物学、化学和药理学领域。Gliovirin是一种新的化合物，具有挑战性的合成靶点和显著的生物活性。该天然产物的全合成将建立可靠的反应来构建复杂的分子结构，并为进一步的生物学评价提供材料。Ceanothine D是从北美东部和中部土着的鼠李属开花成员中分离出来的。在南北战争期间，这种植物的叶子被用作茶的替代品，这种冲泡的茶被认为有降血压的作用。这种植物的药用价值值得对其产生治疗效果的化学物质进行研究。它的历史背景和潜在的生物活性使海洋肽D成为一个有趣的靶点。marinopyroroles是具有挑战性的合成靶点的抗菌结构，在治疗MRSA（耐药葡萄球菌感染）这一临床和社会学相关的疾病状态中显示出新的生物学机制。学生和普通民众的科学教育对社会的未来很重要。基础化学研究为科学教育提供了平台。拟议的计划为基础研究提供了通往高级研究领域的肥沃土壤。提出的兴趣领域将提供可能产生新的科学突破的知识。更重要的是，拟议的研究将有助于许多学生的教育和未来，包括妇女和少数民族，他们从以前的NSF奖中受益。

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.