TOTAL SYNTHESIS OF QUASSINOIDS AND VIRGINIAMYCIN

苦木素和维吉尼亚霉素的全合成

• 批准号: 3279193
• 负责人: RICHARD H SCHLESSINGER
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1988-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3279193
• 关键词: antineoplastic antibiotics; atomic absorption spectrometry; cyclohexane /cyclohexene carboxylate; cytotoxicity; drug design /synthesis /production; drug metabolism; lactones; sesquiterpenes

A total synthesis of the highly cytotoxic pentacyclic diterpene, quasimarian is proposed. Starting from D-(+)-glucose, we intend to prepare a monocyclic alpha-methylene-3-oxycyclopentanone which contains a total of three chiral centers together with a remote diene function. The preparation of this monocyclic species will utilize some aldol chemistry which has been developed in our laboratories. Intramolecular [4 + 2] cycloaddition of this monocyclic substance is expected to occur in the exo-mode--closely following the stereochemical outcome of our own work on the sesquiterpene, quadrone as well as the work of others. The cycloaddition reaction yields a total of five chiral centers contained in a tricyclic framework which represents rings B, C, and E of the target natural product. Of particular importance is the securement of all three sites of oxygenation in ring C in the correct stereochemical arrangement. Further, the tircyclic substance contains both functionality and molecular geometry suitable and conducive to the annulative elaboration of the rings A and D present in this pentacyclic diterpene. A new reaction sequence resulting in the formation of ring A will be used. We also propose a total synthesis of the biologically very interesting macrocyclic antibiotic, virginiamycin. We have divided this molecule into two portions and named them the upper and lower halves. The upper fragment utilizes some new and very useful erythro aldol methodology which features the aldol-lactonization reaction of a vinylogous urethane. The methodology should permit an extremely brief and efficient construction of the upper half of virginiamycin. The lower fragment will be prepared from glutamic acid and takes advantage of some sulfur based methodology we, and other, developed some time ago. We have never used this methodology in a serious synthetic setting and hope to do so during the course of our work on this problem.

高细胞毒性五环二萜的全合成， 拟序的提出。 从D-（+）-葡萄糖开始，我们打算制备 单环α-亚甲基-3-氧基环戊酮，其总共含有 三个手性中心连同远程二烯官能团。 的 这种单环物质的制备将利用一些羟醛化学 这是我们实验室研发的 分子内[4 + 2] 这种单环物质的环加成预计将发生在 exo-mode-密切关注我们自己的工作的立体化学结果， 倍半萜、四酮以及其他人的工作。 的 环加成反应产生总共五个手性中心， 三环框架，其代表靶的环B、C和E 天然产物 特别重要的是确保所有三个 C环中的氧合位点以正确的立体化学排列。 此外，三环物质含有官能度和分子量两者。 几何形状适合并有助于环的环形加工 A和D存在于这个五环二萜中。 一个新的反应序列 将使用导致形成环A的。 我们还提出了一个生物学上非常有趣的全合成 大环抗生素维吉尼亚霉素 我们把这个分子分成 两个部分，并将其命名为上半部分和下半部分。 上层碎片 利用了一些新的和非常有用的羟醛缩合方法， 乙烯基氨基甲酸酯的羟醛-内酯化反应。 的方法 应该允许鞋面的极其简短和有效的构造， 一半维吉尼亚霉素 下面的片段将从谷氨酸制备 酸并利用一些基于硫的方法，我们，和其他， 开发了一段时间。 我们从来没有在一个严肃的问题上使用过这种方法。 合成设置，并希望在我们的工作过程中这样做， 问题.