Investigations of Marine and Terrestrial Natural Products

这项研究计划探索新分子的合成和方法学研究。这些新的天然产物包括格列韦林、头孢诺辛D和马林吡咯。方法学研究将涉及三取代氮杂环开环反应的机理研究和进一步的应用。格列韦林以其生物活性而闻名，但它从未被合成过。拟议的合成策略将探索呋喃Diels-Alder反应，该反应可能被证明适用于其他结构相似的化合物。Ceanothine 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。第一个将使用之前开发的氮杂环丙烷开放方法学来研究一种新的策略。第二种方法将涉及一种更传统的综合战略。产品的绝对配置也将被确定。三取代氮杂环丙烷开环反应的研究将继续进行。该反应在四元中心的立体选择性合成中显示出良好的应用前景。将不同的亲核剂应用于这些氮杂环丙烷，将有助于阐明反应机理，并为其他合成提供手性合成子。卤代吡咯是一类稠密卤代天然产物。这些具有抗菌活性的双吡咯结构表现出轴向手性和双吡咯核心的四氯化。拟议的计划将为这些新的天然产物开发合成策略，扩大当前的方法学研究，并致力于教育学生继续推进有机合成。在化学合成计划的这一奖项的支持下，宾夕法尼亚大学化学系的Madeleine Joullié教授正在探索具有良好生物活性的分子的合成和性质。它们的有效和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，影响到生物、化学和药理学领域。格列韦林是一种新型化合物，具有显著的生物活性，是一个具有挑战性的合成靶点。这种天然产物的完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是从原产于北美东部和中部的沙棘家族的一个开花成员中分离出来的。这种植物的叶子在内战期间被用作茶的替代品，这种啤酒被认为有降血压的作用。这种植物的药用价值需要对其治疗效果的化学物质进行调查。它的历史背景和潜在的生物活性使其成为一个有趣的靶标。马林吡咯是一种抗菌结构，代表了具有挑战性的合成靶点，并在治疗耐药葡萄球菌感染(MRSA)方面显示了一种新的生物学机制，MRSA是一种临床和社会学相关的疾病状态。对学生和普通民众进行科学教育对社会的未来非常重要。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肥沃的土壤，通向高级研究领域。拟议的感兴趣领域将提供可能出现新的科学突破的知识。更重要的是，拟议的研究将有助于包括女性和少数族裔在内的许多学生的教育和未来，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.