Synthetic studies of hybrid macrolides.

本研究的目的是开发一种新的合成方法，一系列复杂的天然和人工大环内酯，通过方便和有效的合成许多片段和它们的耦合从廉价的材料，如葡萄糖开始。1.天然大环内酯类化合物的合成研究：近年来，我们发展了两种大环的合成方法：开环酸的大环内酯化和开环膦酸酯的Horner-Emmons环化。这种方法，结合计算机辅助构象分析（使用分子力学和分子轨道计算）和关键中间体的结构设计，被成功地应用到一个高效的合成18元内酯的tedanlitazone，抗肿瘤的海洋大环内酯。2.人工大环内酯类化合物的合成研究：通过将相应的两个片段偶联，然后进行Horner-Emmons环合反应，合成了烯酮和双烯酮型的典型大环内酯类化合物，如甲炔醚、吡克龙醚、泰勒酮、碳内酯等。为了获得人工大环内酯，尝试了片段组合的交换，但迄今为止只有少数成功的结果。

The purpose of this research was to develop a new synthetic methodology of a series of complex natural and artificial macrolides through convenient and efficient syntheses of many fragments and their couplings starting from inexpensive materials such as glucose. The following three results were mainly obtained during the past three years research.1.Synthetic studies of natural macrolides : Recently, we developed two methods for the constructioi on of macro-rings ; macrolactonization and Horner-Emmons cycization of the corresponding seco acids and aldehyde-ketophosphonates, respectively. This methodology, combined with computer aided conformational analysis (using both molecular mechanics and molecular orbital calculations) and structural design of key intermediates, was successfully applied to a highly efficient synthesis of the 18-membered lactone of tedanolide, an antitumor marine macrolide. The improved synthesis of key fragments of tedanolide was also completed.2.Synthetic studies of artificial macrolide : The enone and dienon type typical macrolides such as methynolide, pikronolide, tylonolide, carbonolides were aynthesized via coupling of the corresponding two fragments followed by Horner-Emmons cyclization. In order to obtain artificial macrolides, exchange of fragment combinations were tried, but only a few successful results were so far available.