Cyclopentannelation in Total Synthesis

全合成中的环戊烷化

• 批准号: 6615543
• 负责人: Marcus Antonius Tius
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6615543
• 关键词: antibiotics; biological products; cyclization; cyclopentane; drug design /synthesis /production; heterocyclic polycyclic compound; stereochemistry

DESCRIPTION: (provided by applicant) Brief enantioselective total syntheses of nakadomarin A and of guanacastepene have been proposed in which the asymmetric cyclopentannelation is the key step. Nakadomarin A, which has been isolated from an Okinawan Amphimedon sp. sponge in 1997 is biosynthetically related to the manzamines, but is structurally without precedent. It has a fairly complicated bridged system of six heterocyclic and carbocyclic rings. It is cytotoxic in the L1210 assay (IC50 1.3 microg/mL), shows inhibitory activity against cyclin dependent kinase 4 (IC50 = 9.9 microg/mL), and has antibacterial and antifungal activity. Guanacastepene, which was isolated in 2000 from an endophytic fungus from a tree in Costa Rica, also has a unique carbon skeleton. It is active against both methicillin-resistant S. aureus (MRSA) and against vancomycin-resistant Enterococcus faecalis (VREF). The absolute stereochemistry of both compounds is in doubt, so the total synthesis will also constitute a proof of structure. Both natural products are structurally unique, therefore they may exert their respective activities through unusual mechanisms. Cancer and multi-drug-resistant human pathogens are two areas of concern in public health. In parallel with the total syntheses we will work to improve the methodology which was developed during the first funding cycle, and expand its scope. A long-range goal of the work is to determine whether the basic method can be adapted for the enantioselective synthesis of compounds with contiguous quaternary carbon atoms. This is still a difficult problem in synthesis.

描述：（由申请人提供）简要对映选择性全合成 nakadomarin A 和 guanacasstepene 已被提出，其中不对称 环戊烷化是关键步骤。 Nakadomarin A，已分离 来自冲绳 Aphimedon sp。 1997年的海绵与生物合成有关 曼扎明，但在结构上是没有先例的。它有一个相当 六个杂环和碳环的复杂桥接系统。这是 L1210 测定中具有细胞毒性（IC50 1.3 microg/mL），显示出抑制活性 对抗细胞周期蛋白依赖性激酶 4 (IC50 = 9.9 microg/mL)，并具有抗菌作用 和抗真菌活性。胍那卡斯特烯 (Guanacasstepene)，2000 年从 来自哥斯达黎加一棵树的内生真菌，也具有独特的碳骨架。 它对耐甲氧西林金黄色葡萄球菌 (MRSA) 和 耐万古霉素粪肠球菌 (VREF)。绝对立体化学 两种化合物的性质尚存疑问，因此全合成也将构成 结构证明。这两种天然产物在结构上都是独特的，因此 他们可能通过不寻常的机制开展各自的活动。癌症 和多重耐药人类病原体是公众关注的两个领域 健康。 在进行全合成的同时，我们将努力改进方法 该计划是在第一个融资周期内制定的，并扩大了其范围。一个 工作的长期目标是确定基本方法是否可以 适用于具有连续结构的化合物的对映选择性合成 季碳原子。这仍然是合成中的一个难题。