Chiral Synthesis of Natural Products Using Microbial Reduction

本项目旨在通过广泛使用微生物还原作为手性诱导方法来合成各种天然产物.研究了对映选择性合成具有强细胞毒活性的奥克拉菌素A。以（-）-香茅醇为起始原料，通过面包酵母还原、不对称双羟基化和立体选择性硼氢化反应，建立了一条合成Buszek's中间体的有效路线.开发了一种高效的伯醇转化为末端烯烃的新方法。该方法包括用n-BuLi简单处理伯醇的苄基醚，并以高产率获得相应的末端烯烃。该反应成功地应用于合成octalactin A.3。Quassiol A是具有五个手性中心的无环三萜醚，其绝对构型尚未确定。利用酵母还原法手性诱导，对映选择性地合成了三种非对映体。根据光谱性质和旋光度，提出了天然苦木醇A的绝对结构.研究了具有8个手性中心的无环三萜醚--桉烯的对映选择性合成。以面包酵母不对称还原得到的同一化合物为原料，成功地合成了两个C_<15>-片段。目前正在进行这些部分的连接。本文报道了一种对海星原肠胚形成有强烈抑制作用的不规则三萜类化合物--海松酸的合成及其绝对立体结构的测定。以月桂烯为起始原料，通过外消旋体的合成，确立了合成路线。利用酵母还原法合成光学活性化合物是一个关键步骤，目前已进入最后阶段。

This project aimed to synthesize various natural products by the extensive use of microbial reduction as the chirality induction method.1. Enantioselective synthesis of octalactin A exhibiting potent cytotoxic activity was investigated. Starting from (-) -citronellol, an efficient route for the synthesis of Buszek's intermediate was developed by the use of baker's yeast reduction, asymmetric dihydroxylation, and stereoselective hydroboration.2. A new and highly effective method for the conversion of primary alcohols into terminal olefins was developed. The method involves simple treatment of benzyl ethers of primary alcohols with n-BuLi and the corresponding terminal olefins are obtained in high yield. The reaction was successfully applied in the synthesis of octalactin A.3. Quassiol A is an acyclic triterpene ether having five chiral centers whose absolute configuration has not been determined. By using yeast reduction as the chirality induction method, three diastereomers were synthesized enantioselectively. On the basis of spectral properties and optical rotations, the absolute structure of natural quassiol A was proposed.4. Enantioselective synthesis of eurylene, an acyclic triterpene ether having eight chiral centers, was studied. From the same compound obtained by the asymmetric reduction with baker's yeast, two C_<15>-segments was synthesized simultaniously. The coupling of these segments is currently under proceeding.5. Synthesis and the determination of absolute stereostructure of hippospongic acid, an irregular triterpenoid which inhibits the gastrulation of starfish potently, were examined. The synthetic route starting from myrcene has been established by the synthesis of racemic compound. The synthesis of optically active compound using yeast reduction as a key step is now at the final stage.