Synthetic research of macrolide and polyether antibiotics.

本研究的目的是促进现代精细有机合成化学的进步，通过开发一种新的方法来选择性和高效地合成非常复杂的分子，如大环内酯、聚醚抗生素和海洋聚醚大环内酯，作为创造新药的基础。在近三年的研究中，主要取得了以下三个成果：1.研究结果：大环内酯类化合物的合成：借助MM2-CONFLEX3计算和仲酸衍生物的NMR分析，通过极高效的大环烷基化合成了最重要的糖基红内酯A。通过16元宏观环的构象控制，carbomycin系列中具有代表性的糖基化合物carbonolide A、leuconolides和maridonolides也完全立体选择性地从carbonolide B合成。应用计算机辅助构象分析和关键中间体设计成功地合成了抗肿瘤海洋大环内酯丹丹内酯，并高效合成了18元内酯。聚醚的合成：用一种新的方法构建取代四氢呋喃和四氢吡喃环以及MPM型保护基团，用常规的方法完成了高度立体选择性的络合物异丙酸A、激光酸A、盐霉素和溶色素的合成。聚醚-大环内酯的合成：立体选择性合成了软海绵素B的四个片段（I: C1-C15, II: C16-C26, III: C27-C36, IV: C37-C54），完成了片段间的偶联，得到了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。

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.