Highly stereoselective synthesis of complex natural products.

本研究的目的是从葡萄糖等廉价原料出发，通过方便、高效地合成许多片段及其偶联产物，开发一种新的合成方法来合成一系列复杂的天然大环内酯类化合物。在过去三年的研究中，我们主要取得了以下成果：最近，我们开发了两种方法来构建大环：相应的二羧酸和醛酮基膦酸酯的大内酯化和Horner-Emmons环化。这种方法与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相结合，现在被应用于抗肿瘤海洋大环内酯--替丹内酯的合成研究。以羟基异丁酸甲酯为起始原料，立体选择性地合成了两个片段，分别为C_1-C_(12)和C_(13)-C_(23)，并偶联成二酸，该二酸可有效地转化为18个基团的内酯，内酯是合成替丹内酯的关键中间体。还完成了新片断的立体选择性合成，这些片断将转化为另一种二酸、相应的内酯和更合理的tedanolide。

The purpose of this research was to develop a new synthetic methodology of a series of complex natural macrolides through convenient and efficient syntheses of many fragments and their couplings, starting from inexpensive materials such as glucose. The following results were mainly obtained during the past three years research.Recently, we developed two methods for the construction of macro-rings ; macrolactonization and Horner-Emmons cyclization 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 now applied to synthetic studies of tedanolide, an antitumor marine macrolide. Two fragments, C1-C12 and C13-C23, were synthesized stereoselectively staring from methyl hydroxyisobutyrates and coupled to give a seco-acid, which converted efficiently to an 18-mombered lactone, a key intermediate for the synthesis of tedanolide. Stereoselective syntheses of new fragments, which will be converted to another seco-acid, the corresponding lactone, and tedanolide more reasonably, were also completed.