SYNTHESIS OF MACROLIDES, STEROIDS, CYCLOPENTANOIDS ETC.

大环内酯类、类固醇类、环戊类化合物等的合成

• 批准号: 3484163
• 负责人: BARRY M TROST
• 金额: $ 28.35万
• 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 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3484163
• 关键词: amphotericin B; antifungal agents; antineoplastics; beta lactam antibiotic; conformation; cyclopentane; cytochalasins; drug design /synthesis /production; drug screening /evaluation; eicosanoid metabolism; ergosterol; fatty acid biosynthesis; female antifertility drug; osteoporosis; photochemistry; picrotoxin; progesterone; prostaglandin analogs; steroid biosynthesis; steroids; vitamin D

The aim of this proposal is to develop facile synthetic entries into various classes of biologically active molecules. We are examining the question of whether tailor-made transition metal complexes may serve as templates to control selectivity in a way reminiscent of enzymes. The first section deals with the development and understanding of metal catalyzed cyclizations at high substrate concentration and with high control stereochemistry to form medium and large ring carbo- and heterocycles whose biological functions include antibiotic and antifungal activity. Some example are: 1) a 9-membered carbocyclic ring such as pachyaldehyde, a representative of a family of antimicrobial marine natural products, 2) a 10- membered macrolide such as the antibiotic cephalosporilide C, 3) an 11-membered carbocyclic ring such as the antibiotic aspochalasin B, 4) a 12-membered metal bridged aryl cyclic ether such as the PG synthetase inhibitor arnebinol, 5) the 14 - membered macrolide portion of the cytochalasin antibiotics, 6) The 17-membered para bridged antibiotic lankacidin C, and 7) The 36-membered ring system of amphotericin B, a clinically important antifungal compound. Cyclopentanes are a structural type of exploding biological significance. Delicate selectivity in cyclizations will be explored in the case of the antifungal terpene chokol C, the antimicrobials udoteatrial and petiodial, the antibiotics enterocine and merulidial, the pharmacologically important picrotaxane neurotoxins, the anticonvulsant anisatin, the antibiotics punctatin A and mellodonal, and retigeranic acid. Mimicking enzymes with transition metal templates is examined to improve selectivity in cycloadditions to five-membered rings. Enzymes use substrate structural features remote from the reaction center to control conformation and thus selectivity; the specific introduction of such remote binding sites will be developed for controlling cycloadditions. Especially relevant is use of gamma -alkoxy -alpha, beta -unsaturated sulfones for 1) asymmetric cyclopentenone annulation, 2) carbacyclin and prostaglandin synthesis, and 3) a synthesis of ginkgolide A, a PAF inhibitor. The third section encompasses steroids and related terpenes using related methodology. A short asymmetric synthesis of the A ring and a totally new metal catalyzed reaction for forming the CD rings of the clinically important Vitamin D metabolites will examined. Closely related chemistry offers a simple strategy to the novel and clinically important antifungal sicannin. The fourth section extends these new synthetic concepts to the beta-lactam antibiotics.

该提案的目的是开发简单的合成条目， 各种生物活性分子。 我们 研究定制的过渡金属 复合物可以作为模板以某种方式控制选择性 让人联想到酶。 第一部分涉及 金属催化环化反应的发展和认识. 高底物浓度和高控制 立体化学以形成中等和大环碳-和 杂环，其生物学功能包括抗生素和 抗真菌活性 一些例子是：1）9元 碳环如茯苓醛，其代表是 抗微生物海洋天然产物家族，2）10- 元大环内酯类，如抗生素头孢菌素C，3） 11元碳环，如抗生素 Aspochalasin B，4）12元金属桥连的芳基环醚 如PG合成酶抑制剂arnebinol，5）14 - 细胞松弛素类抗生素的三员大环内酯部分，6） 17元帕拉桥连抗生素lankacidin C，和7） 36-一种具有临床意义的抗生素--阿替霉素B， 重要抗真菌化合物。 环戊烷是一种结构类型的爆炸生物 意义 将探讨环化反应中的精细选择性 在抗真菌萜烯Chokol C的情况下， 子宫内膜和叶柄，抗生素肠肽和 merulidial，非常重要的picrotaxane 神经毒素，抗惊厥药茴香素，抗生素 美洛酮和瑞替格尔酸。 研究了以过渡金属为模板的模拟酶 以提高对五元环的环加成反应的选择性。 酶利用远离底物的结构特征， 反应中心来控制构象和选择性; 这种远程结合位点的具体引入将 用于控制环加成反应。 特别相关的是 γ-烷氧基-α，β-不饱和砜用于1） 不对称环戊烯酮成环，2）碳环素和 前列腺素合成，和3）银杏内酯A，PAF的合成 抑制剂. 第三部分包括类固醇和相关的萜烯， 相关方法。 A环的不对称短合成 和一种全新的金属催化反应形成CD 临床上重要的维生素D代谢物的环将 考察 密切相关的化学提供了一个简单的策略， 新的和临床上重要的抗真菌sicannin。 第四部分将这些新的综合概念扩展到 β-内酰胺类抗生素