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Synthesis of Biologically Active Compounds via Novel Synthetic Reactions Using Lewis Acids

使用路易斯酸通过新型合成反应合成生物活性化合物

基本信息

批准号：
04555205
负责人：
SAIGO Kazuhiko
金额：
$ 2.43万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

Based on the investigation of novel synthetic reactions using Lewis acids, we examined the reactions between 2,2-dialkoxycyclopropanecarboxylic esters and carbonyl compounds. The reaction with aldehydes gave cis-3,4-substituted-gamma-lactones with high selectivities in the presence of titanium tetrabromide or tin tetrabromide as a Lewis acid.Furthermore, the reaction between s ymmetric ketones and 3-mono-substituted cyclopropanes gave cis-2,3-substituted-gamma-lactones in high yields with high stereoselectivities.Next, we tried to control tree continuous asymmetric centers in a lactonering. As a result, we found that 2,3-cis, 3,4-trans-tri-substituted gamma-lactones were synthesized with high selectivities by using zirconium tetrachloride as an activator.Using this methodology, the synthesis of dihydropertusaric acid, isolated from a lichen, was performed.However, the stereochemical assignment of the naturally occurring lactone was found to be incorrect. Namely the natural compound has 2,3-trans, 3,4-cis configuration, which is not a suitable stereoisomer for the present reaction. Then, we could not synthesize a natural product, but established a simple and stereoselective route to unnatural dihydropertusaric acid and a method for the optical resolution of its racemate. However, the lactones as well as its synthetic intermediates indicated less bioactivity, such as antifungal activity, than we anticipated.Furthermore, we tried the reactions mediated by divalent germanium species and found that it could be utilized in the Barbier type reaction.Namely, allylgermanium (IV) reagents, generated in situ from germanium (II) iodide and allylic halides, reacted with carbonyl compounds to give homoallylic alcohols.

在对Lewis酸合成新反应研究的基础上，我们考察了2，2-二烷氧基环丙烷羧酸酯与羰基化合物的反应。在四溴化钛或四溴化锡存在下，与醛反应生成高选择性的顺-3，4-取代-伽马-内酯，再通过S对称酮与3-单取代环丙烷的反应，高产率地得到立体选择性高的顺-2，3-取代-伽马-内酯。结果发现，以四氯化锆为活化剂，高选择性地合成了2，3-顺，3，4-三取代伽马-内酯，并用此方法合成了从地衣中分离出来的二氢过水杨酸，但对天然产物内酯的立体化学归属不正确。也就是说，天然化合物具有2，3-反式，3，4-顺式构型，这不是适合本反应的立体异构体。然后，我们不能合成天然产物，而是建立了一条合成非天然二氢过水杨酸的简单、立体选择性的路线及其外消旋的光学拆分方法。然而，内酯及其合成的中间体显示出比我们预期的更弱的生物活性，如抗真菌活性。此外，我们尝试了二价锗物种介导的反应，发现它可以用于Barbier类型的反应。