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

在研究Lewis酸合成新反应的基础上，研究了2,2-二氧环丙羧酸酯与羰基化合物之间的反应。在四溴化钛或四溴化锡作为路易斯酸存在下，与醛反应得到具有高选择性的顺式-3,4-取代-内酯。此外，5不对称酮与3-单取代环丙烷反应生成了具有高立体选择性的顺式2,3取代-内酯。接下来，我们尝试在内酯化过程中控制3个连续的不对称中心。结果表明，以四氯化锆为活化剂，可以高选择性地合成2,3-顺式，3,4-反式三取代的γ -内酯。用这种方法合成了从地衣中分离得到的二氢百日咳酸。然而，发现天然存在的内酯的立体化学分配是不正确的。即天然化合物具有2,3-反式，3,4-顺式构型，不适合作为本反应的立体异构体。然后，我们不能合成天然产物，但我们建立了一个简单的立体选择性的非天然二氢百日咳酸的路线和它的外消旋体的光学分辨方法。然而，内酯及其合成中间体显示出较低的生物活性，如抗真菌活性，比我们预期的。此外，我们尝试了二价锗介导的反应，发现它可以用于Barbier型反应。也就是说，由碘化锗（II）和烯丙基卤化物原位生成的烯丙基锗（IV）试剂与羰基化合物反应生成均烯丙基醇。

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.