APPLICATIONS OF IRON COMPLEXES TO ORGANIC SYNTHESIS

铁配合物在有机合成中的应用

• 批准号: 2851753
• 负责人: William A Donaldson
• 金额: $ 14.05万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2851753
• 关键词: alkylation; antibacterial agents; antibiotics; antifungal agents; antiviral agents; biological products; chemical synthesis; cyclopropanes; diene; drug design /synthesis /production; iron compounds; metal complex; polyenes; stereochemistry

The long range goal of our research is to develop new synthetic methodology for the construction of C-C bonds in a stereospecific fashion. This new methodology will be useful for the preparation of polyene macrolides and for the preparation of cyclopropane containing natural products. In particular, we wish to utilize the ability of an ironcarbonyl adjunct: a) to control the stereochemistry of conjugated dienes and to protect the diene against reduction oxidation, and cycloaddition reactions; b) to control the relative stereochemistry at asymmetric centers adjacent and remote to a conjugated diene; c) to control the relative stereochemistry of trisubstituted cyclopropanes; d) to control the relative stereochemistry at asymmetric centers adjacent to a trans-disubstituted cyclopropane. As vehicles for demonstration of these methodologies, we have chosen macrolactin A, madumycin II, ambruticin, 2-(2'- carboxycyclopropyl) glycines, and FR-900848 as targets. Macrolactin A was isolated from an unidentified deep sea bacterium. This compound exhibits antiviral activity against Herpes Simplex I and II and against HIV in initial tests. Since the culturing of this bacterium has been "unreliable", further biological research must rely on total synthesis. Madumycin II is a member of the streptogramin A family of antibiotics which are active against Gram-positive organisms. Ambruticin is a structurally complex antifungal agent. This compound was found to be orally active against systemic infections of histoplasmosis and coccidiomycosis. Several 2-(2'-carboxycyclopropyl)glycines have been found to be potent ligands for metabotropic glutamate receptors. FR-900848 is a polycyclopropane molecule isolated from the fermentation of Streptoverticillium fevens which inhibits filamenteous fungi such as Aspergillus niger, but has relatively low toxicity in mammals (LD50 greater than 1g/1kg).

我们研究的长远目标是开发新的合成药物。 在立体有择的化合物中构建C-C键的方法 时尚. 这一新方法将有助于编写 多烯大环内酯和用于制备含环丙烷的 天然产品。 特别是，我们希望利用一个 羰基铁辅助剂：a）控制共轭铁的立体化学 二烯并保护二烯免受还原氧化，和 环加成反应; B）控制在 邻近和远离共轭二烯的不对称中心; c） 控制三取代环丙烷的相对立体化学; d）控制不对称中心处的相对立体化学 与反式二取代的环丙烷相邻。 作为演示这些方法的工具，我们选择了 macrolactin A，madumycin II，ambruticin，2-（2'-carboxyclocyclopropyl） 甘氨酸和FR-900848作为靶标。巨乳素A是从一种 未知的深海细菌 这种化合物具有抗病毒作用 抗单纯疱疹病毒I型和II型以及抗艾滋病毒的活性， 试验. 由于这种细菌的培养一直“不可靠”， 进一步的生物学研究必须依靠全合成。 马杜霉素II 是链阳菌素A抗生素家族的一员， 对革兰氏阳性菌有活性。 Ambruticin是一种结构上 复合抗真菌剂。 发现该化合物具有口服活性 抗组织胞浆菌病和球孢子菌病的全身感染。 已经发现几种2-（2 '-羧基环丙基）甘氨酸是有效的 代谢型谷氨酸受体的配体。 FR-900848是一种 多环丙烷分子分离的发酵， 黄轮枝链霉菌抑制丝状真菌， 尼日尔曲霉，但对哺乳动物的毒性相对较低（LD 50 大于1g/1 kg）。