Synthetic research of macrolide and polyether antibiotics.

这项研究的目的是通过发展一种新的方法来选择性和高效地合成非常复杂的分子，如大分子化合物、聚醚抗生素和海洋聚醚大环内酯类化合物，以促进现代精细有机合成化学的进步，作为创造新药的基础。在过去三年的研究中，主要取得了以下三个方面的成果。大环内酯类化合物的合成：通过MM2-CONFLEX3计算和二酸衍生物的核磁共振分析，通过非常有效的大乳化法，完成了一种新的立体选择性地合成了最重要的配基--红内酯A。以碳内酯B为原料，通过16元大环的构象控制，完全立体选择性地合成了具有代表性的卡霉素类配基化合物，如碳内酯A、亮糖内酯和大蒜素内酯。结果1.成功地将计算机辅助构象分析和关键中间体结构设计应用于抗肿瘤海洋大环内酯类化合物的立体选择性合成，并高效地合成了18元内酯。聚醚的合成：采用一种新的构筑取代四氢呋喃和四氢吡喃环及MPM型保护基团的新方法，完成了复合异抗菌素A、拉沙洛菌素A、盐霉素和溶菌素的高立体选择性合成。聚醚-大环内酯类化合物的合成：立体选择性地合成了四个灯盏花素B片段(I：C1-C15，II：C16-C26，III：C27-C36，IV：C37-C54)，并在片段之间偶联得到了C1-C36和C16-C54中间体。为了完成灯盏花素B的全合成，目前正在进行最后的偶联反应。

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.