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.

高度细胞毒性的五乙二醇二萜的总合成， 提出了准疗法。 从d - （+） - 葡萄糖开始，我们打算准备 单核α-甲基-3-氧环戊酮，总共包含 三个手动中心与远程二元函数一起。 这 这种单核种类的制备将利用某些藻类化学 这是在我们的实验室中开发的。 分子内[4 + 2] 预计该单核细胞的环加成会发生在 Exo Mode-诚实地遵循我们自己工作的立体化学结果 倍半萜，二极管以及他人的工作。 这 环加成反应产生了A中总共五个手动中心 三环框架，代表目标的环，c和e 天然产品。 特别重要的是这三个 在正确的立体化学排列中，环C中的氧合位点。 此外，Tircyclic物质既包含功能和分子 几何形状适合淘汰环的阐述 A和D存在于此五乙烯中。 一个新的反应序列 将使用环A的形成。 我们还提出了生物学上非常有趣的完全合成 大环抗生素，牙氨霉素。 我们已经将这个分子分为 两部分并将其命名为上半部分。 上部碎片 利用一些具有特征的新的且非常有用的Erythro Aldol方法论 乙烯基氨基甲烷的醛醇 - 乳化反应。 方法 应允许上鞋面的短暂和高效的构造 一半的牙氨霉素。 下部片段将从谷氨酸制备 酸并利用某些基于硫的方法论我们和其他方法 一段时间以前开发。 我们从来没有认真使用这种方法 合成环境，并希望在我们的工作过程中这样做 问题。