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Synthetic research of macrolide and polyether antibiotics.

大环内酯类和聚醚类抗生素的合成研究。

基本信息

批准号：
04557096
负责人：
YONEMITSU Osamu
金额：
$ 7.55万
依托单位：
Okayama University of Science (1994)Hokkaido University (1992-1993)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

The purpose of this research was to contribute to the progress of modern fine organic synthetic chemistry as a basis of the creation of new medicines throrgh the development of a new methodology for selective and efficient syntheses of very complex molecules such as macroide, polyether antilbiotics and marine polyether-macrolides. During the past three years research the following three results were mainly obtained.1. Synthsis of macrolides : A new stereoselective syntheses of erythromolide A,the most important aglycon, was completed via an extremely efficient macrolactionization with the aid of MM2-CONFLEX3 calculation and NMR analysis of seco-acid derivatives. The representative aglycons in carbomycin series such as carbonolide A,leuconolides, and maridonolides were also synthesized completely stereoselectively from carbonolide B through conformational control of 16-membered macro-rings. Computer-aided conformational analysis and structural design of key intermediates for the stereoselective synthesis of tedanolide, an anti-tumor marine macrolide, were successfully applied, and an 18-membered lactone was synthesized highly efficiently.2. Synthesis of polyethers : Highly stereoselective syntheses of complex isolasalocid A,lasalocid A,salinomycin, and lysocellin by a common methodology using a new method for the construction of substituted tetrahydofuran and tetrahydropyran rings and MPM type protective groups were completed.3. Synthesis of polyether-macrolides : Four fragments (I : C1-C15, II : C16-C26, III : C27-C36, IV : C37-C54) of halichondrin B were stereoselectively synthesized, and couplings among the fragments were completed to give C1-C36 and C16-C54 intermediates. In order to complete the total synthesis of halichondrin B final couplings are now in progress.

本研究的目的是通过发展一种选择性和高效合成大环内酯、聚醚类抗生素和海洋聚醚-大环内酯等复杂分子的新方法，为现代精细有机合成化学的发展做出贡献，为新药的开发奠定基础。在过去三年的研究中，主要取得了以下三个方面的成果.大环内酯类的合成：利用MM ~ 2-CONFLEX ~ 3计算和开环酸衍生物的NMR分析，通过高效的大环内酯化反应，实现了一种新的立体选择性合成赤藓醇内酯A的方法。碳霉素系列中的代表性糖苷配基如碳环内酯A、明串珠内酯和玛丽多内酯也是通过16元大环的构象控制从碳环内酯B完全立体选择性地合成的。成功地应用计算机辅助构象分析和关键中间体结构设计，立体选择性合成了抗肿瘤海洋大环内酯类化合物替丹明，高效合成了18元内酯.聚醚的合成：采用一种新的方法构建取代的四氢呋喃环和四氢吡喃环以及MPM型保护基，通过常规方法高立体选择性地合成了isolasalocid A，lasalocid A，salinomycin和lysocellin.聚醚-大环内酯的合成：立体选择性地合成了软海绵素B的四个片段（I：C1-C15，II：C16-C26，III：C27-C36，IV：C37-C54），并完成片段之间的偶联，得到C1-C36和C16-C54中间体。为了完成软海绵素B的全合成，目前正在进行最后的偶联。