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Synthetic Study on Taxol via a New Route Inspired by Its Biogenesis

紫杉醇生物起源启发的新路线合成研究

基本信息

批准号：
12672072
负责人：
NAKADA Masahisa
金额：
$ 1.86万
依托单位：
Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

In the synthetic study on taxol arose from the interest in its biosynthetic pathway found was the condition for the coupling reaction of the Left-Wing with the Right-Wing model compound, and the transformation of the coupled products to the substrate for the designed transannular reaction. Though the undesired product was the major product, the desired 10-membered ring formed in 10 % yield by the intramolecular pinacol coupling between C-9 and C-10. Hence, another position should be selected if the ring closure is to be carried out by the intramolecualr pinacol coupling. The B-ring closure by the intramolecular alkylation of the cyanohydrin was examined, too. Though its yield was not determined because the reaction was run in a small scale, almost no side products formed in this reaction. Hence, this method will be a promising one if the reaction condition is optimized.In the synthetic study on taxol directed towards its efficient synthesis found was that two model keto-aldehydes afforded the desired products in 12 % and 20 % (at 91 % conversion) yields. The keto-aldehyde possessing acetonide between C-9 and C-10 diol, which was designed to make the reaction points come closer, was also examined, but the corresponding diol was a sole product in this case. Another keto-aldehyde possessing sp^2 C-11 carbon was prepared and subjected to the intramolecular pinacol coupling, but no desired product was obtained.From the results obtained in this study, we recognized that a proper devise to promote the intramolecular pinacol coupling between C-9 and C-10 must be set in the substrate to achieve the efficient construction of B-ring. Hence, we are now investigating the intramolecular pinacol coupling of the substrate possessing a hydroxy group at C-16, because this hydroxy group would aid the substrate to take an endo boat-chair conformation in the transition state to afford the desired product.

在对紫杉醇的合成研究中，由于对紫杉醇生物合成途径的兴趣，发现了左旋与右旋模型化合物发生偶联反应的条件，以及偶联产物向设计的跨环反应底物的转化。虽然不需要的产物是主要产物，但通过C-9和C-10之间的分子内频哪醇偶联以10%产率形成所需的10元环。因此，如果环闭合是通过分子内频哪醇偶联进行的，则应选择另一个位置。也检查了由氰醇的分子内烷基化进行的B环闭合。由于反应规模小，产率无法确定，但几乎没有副产物生成。在紫杉醇的合成研究中发现，两种模型酮醛的产率分别为12%和20%（转化率91%）。还考察了在C-9和C-10二醇之间具有丙酮化合物的酮-醛，其被设计为使反应点更接近，但在这种情况下，相应的二醇是唯一的产物。另一种含sp^2碳原子的酮醛经分子内的片呐醇偶联没有得到预期的产物，由此我们认识到，要实现B环的有效构建，必须在底物中设置适当的装置来促进C-9和C-10之间的片呐醇偶联。因此，我们现在正在研究在C-16位具有羟基的底物的分子内频哪醇偶联，因为该羟基将有助于底物在过渡态中采取内船椅构象以提供所需的产物。