SYNTHESIS OF MACROCYCLES STEROIDS CYCLOPENTANOIDS ETC

大环类固醇环戊烷等的合成

• 批准号: 6017041
• 负责人: BARRY M TROST
• 金额: $ 42.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6017041
• 关键词: amphotericin B; antifungal agents; antineoplastics; beta lactam antibiotic; chemical synthesis; cyclopentane; cytochalasins; drug design /synthesis /production; female antifertility drug; macrolide antibiotics; nitrogenous heterocyclic compound; picrotoxin; prostaglandin analogs; steroids; vitamin D

DESCRIPTION: Exploring biological phenomena at a molecular level provides the basis of understanding from which new therapeutic agents derive. The ability to construct a defined molecular architecture requires highly selective reactions and reagents to permit the development of effective synthetic strategies. Cyclic compounds have biological activities across a broad spectrum. Furthermore, constraining conformations of mobile molecules by forming rings also frequently enhances biological potency. Thus, a concerted effort to apply new chemical principles being developed in the PI's laboratories to the formation of rings becomes an important objective. In the first phase, a new concept to create macrocycles (rings larger than seven members) may provide a unique opportunity to approach a variety of significant targets. Some examples include the antiinflammatory nine membered macrolides ascidiatrienolides, the antitumor eight membered carbocycles, the shikoccins, and the azocines, FR-99048 and FR-66979, the ten membered macrolactam neuropeptidase inhibitor CGS-25155,the fourteen membered antiviral and antifungal fluviricinines, and the nineteen membered serine protease inhibitors, the cyclotheonamides. In the second phase, a new reactivity mode for shuffling protons in totally unconventional methods offers novel approaches to cyclizations. Vitamin D analogues and derivatives represent a most important direction for creation of clinically important therapeutic agents. A new concept for their synthesis based upon novel strategies for asymmetric induction will be pursued. A variation on this methodology may extend the reaction to a facile asymmetric synthesis of either cis or trans fused drimanes and related classes of terpenoids from a common intermediate, a class of compounds that have remarkably broad biological activities including antibacterial, antifungal, antimalarial, antiinflammatory, cytotoxic, and insecticidal. A new class of reactions provides a novel atom economical approach for formation of heterocycles. This invention stimulates exploration of a potentially, greatly simplified strategy to the important food toxin, aflatoxin. The envisioned asymmetric route also may provide a simple protocol for the asymmetric synthesis of physostigmines, one of whose members is a candidate for treatment of myasthenia gravis, glaucoma, and Alzheimer's disease. A third phase examines a new class of cycloaddition reactions to create odd membered rings. Exploring a new class of acceptors in conjunction with a novel class of reactive intermediates creates a conceptual framework to the anthelmintic and antinematodal mold metabolites paraherquamide and marcfortine. An unusual (6+3) cycloaddition may create strategies for the structurally unusual farnesyl transferase inhibitor CP-263,114 and simpler analogues. Ring expansion methods may convert these cores into the taxoid skeleton with appropriate functionality at key points for analog development.

描述：在分子水平上探索生物现象， 新的治疗药物的基础。 的 构建确定的分子结构的能力需要高度的 选择性反应和试剂，以允许开发有效的 综合战略。 环状化合物具有跨物种的生物活性。 广谱 此外，限制移动的分子的构象 通过形成环也经常增强生物效力。 因此 协调一致地努力应用正在制定的新的化学原则， PI的实验室对环的形成成为一个重要的目标。 在第一阶段，创建大环的新概念（大于 七名成员）可以提供一个独特的机会， 重要目标。 一些例子包括 抗肿瘤八元大环内酯海鞘三烯内酯 FR-99048和FR-66979， 十元大环内酰胺神经肽酶抑制剂CGS-25155，十四元大环内酰胺神经肽酶抑制剂CGS-25155， 19元抗病毒和抗真菌的氟维蓖麻碱，和19元 丝氨酸蛋白酶抑制剂，环辛酰胺。 在第二阶段，A 在完全非常规方法中重排质子的新反应性模式 提供了新的环化方法。 维生素D类似物和 衍生物代表了临床上创造 重要的治疗药物。 一个新的概念，他们的综合基础上， 将寻求不对称诱导的新策略。 的变型 该方法可以将反应扩展到容易的不对称合成 顺式或反式稠合的补身烷和相关类别的萜类化合物， 常见的中间体，一类化合物，具有非常广泛的 生物活性包括抗细菌、抗真菌、抗疟疾 杀虫、细胞毒和杀虫。 一类新的反应 为杂环化合物的形成提供了一种新的原子经济途径。 本发明刺激了对潜在的、大大简化的 战略的重要食物毒素，黄曲霉毒素。 所设想的不对称 该路线还可以提供用于不对称合成 毒扁豆碱，其中一个成员是治疗 重症肌无力、青光眼和阿尔茨海默病。 第三阶段研究了一类新的环加成反应， 元环 与a结合探索一类新的受体 一类新的活性中间体创建了一个概念框架， 抗蠕虫和抗线虫霉菌代谢物paraherquamide和 marcfortine。 一个不寻常的（6+3）环加成反应可能会产生策略， 结构上不寻常的法尼基转移酶抑制剂CP-263，114和更简单的 类似物 扩环方法可以将这些核心转化为紫杉烷 在关键点具有适当功能的骨架， 发展