Cyclopentannelation in Total Synthesis

描述：(申请人提供)简短的对映体选择性全合成 Nakadomarin A和鸟粪苷类化合物已被提出，其中不对称 环戊烯基化是关键的一步。Nakadomarin A，已分离得到 从一株冲绳双毛虫(Amphimedon sp.)1997年的海绵在生物合成上与 曼扎明，但在结构上没有先例。它有一个相当不错的 六个杂环和碳环的复杂桥联体系。它是 L1210细胞毒(IC50 1.3微克/毫升)，显示抑制活性 抗细胞周期蛋白依赖性激酶4(IC50=9.9微克/毫升)，并具有抗菌作用 和抗真菌活性。瓜纳卡斯汀，于2000年从一种 来自哥斯达黎加一棵树的内生真菌，也有一个独特的碳骨架。 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 这两种化合物的合成都是有疑问的，所以全合成也将构成 结构的证明。这两种天然产物在结构上都是独一无二的，因此 它们可能会通过不寻常的机制开展各自的活动。癌 耐多药的人类病原体是公众关注的两个领域 健康。 在全面综合的同时，我们将努力改进方法学。 它是在第一个供资周期内制定的，并扩大了其范围。一个 这项工作的长远目标是确定基本方法是否可以 适用于邻位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。

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.