ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

全世界约有2.7亿人感染了疟疾，这种疾病导致 每年有100万到200万人死亡。难以克服的问题 在开发疟疾疫苗时遇到的问题，以及疟原虫的能力 恶性疟原虫对新药产生抗药性，刺激了世界 卫生组织和其他机构寻找新的钻机来治疗这种疾病 疾病。青蒿素已成为开发新药的先导化合物 治疗传播到世界各地的恶性疟原虫耐药株 并威胁到印度和非洲。由于没有菌株P. 对青蒿素衍生物产生抗药性的恶性疟原虫已经出现，许多 已制备了衍生物(二氢青蒿素的酯和醚) 在中国和美国。芳香醚的代谢研究 双氢青蒿素衍生物预定进行临床试验，发现它 被迅速脱烷基化为双氢青蒿素。很有可能是 双氢青蒿素的酯被迅速水解成相同的化合物。 为了制备不能降解的化合物 双氢青蒿素，我们引入了额外的官能团 白僵菌微生物介导氧化青蒿素的研究 硫磺。这些羟化材料的衍生物已经被 准备和测试。在第二种方法中，我们用羟基取代 带有烯丙基的双氢青蒿素。烯丙基的双键 取代基使我们能够在分子中引入极性基团，从而 来调整它的亲脂性或亲水性。极性在以下方面很重要 决定管理方式。大多数化合物被发现是 与青蒿素、蒿甲醚具有相同或更好的防治效果。 体外恶性疟原虫。最好的化合物，正丙基衍生物，是 在感染伯氏疟原虫的小鼠身上进行体内测试。

Some 270 million people worldwide are infected with malaria which causes between 1 and 2 million deaths per year. The formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to become resistant to new drugs, has stimulated the World Health Organization and others to search for new drigs to treat this disease. Artemisinin has served as a lead compound to develop new drugs to treat the resistant strains of P. falciparum that have spread ouver southeast Asia and threaten India and Aftica. Since no strains P. falciparum resistant to artemisinin derivatives have appeared, many derivatives (esters and ethers of dihydtoartemisinin) have been prepared in China and the United States. Metabolic studies of arteether, a dihydroartemisinin derivative scheduled for clinical tests, found that it is rapidly dealkylated to dihydroartemisinin. It is very likely that esters of dihydroartemisinin are rapidly hydrolyzed to the same compound. In order to prepare compounds that can not be degraded to dihydroartemisinin, we introduced additional functional groups into artemisinin by a microbially mediated oxidation using Beauveria sulfurescens. Derivatives of these hydroxylated materials hiave been prepared and tested. IN a second approach we replaced by hydroxy group of dihydroartemisinin with an allyl group. The double bond of the allyl substitutent enabled us to introduce polar groups into the molecule so as to adjust its lipo- or hydro-philicity. The polarity is important in deciding the mode of administration. Most of the compounds were found to be as or more effective than artemisinin and arteether against P. falciparum in vitro. The best compound, the n-propyl derivative, is undergoing in vivo testing in mice infected with P. berghei.