STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

这项建议旨在制定新的办法， 天然存在的物质的结构， 生物活性 基于乙烯基乙酰胺的三个研究领域 本文概述了光化学：1）乙烯基的延伸 酰胺光环加成/逆Mannich断裂/闭环 全氢喹啉环体系的合成顺序; 2） 叔乙烯基乙酰胺的光环化加成在 新发现的曼扎明抗肿瘤生物碱的构建; 和3）一种新的合成的范围和局限性的研究， 基于乙烯基酰胺的光化学的杂环化合物。 紫杉醇（NSC-125973）是一种非常有前途的癌症化疗药物 具有异常广谱的强效抗白血病和 肿瘤抑制活性。 它是唯一已知的植物产品， 微管的组装和抑制微管蛋白的解体过程 因此，它似乎是一种新型癌症的原型 化疗剂。 两种方法的建设， 紫杉烷二萜的碳环系统描述于此 建议：1）分子内二恶烯酮的应用 用于合成紫杉醇类似物和天然紫杉醇的光环加成反应 发生紫杉醇;和2）高度收敛的方法的发展 用于合成基于Grob样的紫杉烷二萜， 分子内烯酮-烯烃环加合物的断裂。 本文概述的生物合成策略 活性天然产物在Diels-Alder反应中具有对应物， 阳离子多烯环化、芳烃-烯烃环加成反应。 一个以上的碳-碳键和大量的立体化学 信息在单个合成操作中生成。 的方法 用于构建曼扎明生物碱和紫杉烷二萜， 本提案中概述的内容证明了这方面的巨大潜力。 重要药用物质的合成方法。

This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. Three areas of research based on vinylogous amide photochemistry are outlined herein: 1) the extension of the vinylogous amide photocycloaddition/retro-Mannich fragmentation/ring closure sequence to the synthesis of perhydroquinoline ring systems; 2) the application of the photocycloaddition of tertiary vinylogous amides to a construction of the recently discovered manzamine antitumor alkaloids; and 3) a study of the scope and limitations of a novel synthesis of heterocycles based on the photochemistry of vinylogous amides. Taxol (NSC-125973) is an exceptionally promising cancer chemotherapeutic agent with an unusually broad spectrum of potent antileukemic and tumor-inhibiting activity. It is the only plant product known to promote the assembly of microtubules and inhibit the tubulin disassembly process and, thus, appears to be the prototype of a new class of cancer chemotherapeutic agents. Two approaches for the construction of the carbocyclic ring system of the taxane diterpenes are described in this proposal: 1) the application of the intramolecular dioxenone photocycloaddition to the synthesis of taxol analogs and the naturally occurring taxusin; and 2) the development of a highly convergent approach for the synthesis of the taxane diterpenes based on a Grob-like fragmentation of an intramolecular ketene-olefin cycloadduct. The strategies that are outlined herein for the synthesis of biologically active natural products have counterparts in the Diels-Alder reaction, cationic polyene cyclization, and arene-olefin cycloaddition reaction. More than one carbon-carbon bond and considerable stereochemical information is generated in a single synthetic operation. The approaches for the construction of the manzamine alkaloids and the taxane diterpenes outlined in this proposal attest to the considerable potential of this methodology for the synthesis of medicinally important substances.