ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

在发展疟疾过程中遇到的可怕问题 疫苗，以及恶性疟原虫产生抗药性的能力 到新药，激发了人们对使用药物组合的兴趣 用于治疗这种每年夺走100多万人生命的疾病。 尽管恶性疟原虫菌株已经对多种药物产生了抗药性， 到目前为止，还没有菌株对青蒿素的衍生物产生抗药性。 青蒿素的衍生物被认为破坏了寄生虫的膜， 奎宁或甲氟喹则抑制二氢叶酸还原酶。因此， 寄生虫必须在不同的位置突变才能产生抵抗力 青蒿素。大量的衍生物(乙酸酯和乙醚 双氢青蒿素)已在中国和美国制备 并被证明对恶性疟原虫有活性。对于其他结构- 活性研究，我们想把一个新的官能团引入到 分子，而不破坏其抗疟疾所需的过氧化氢 活动。我们已经调查了真菌白僵菌的能力 硫化试剂在未活化的甲基上引入羟基， 青蒿素衍生物中的亚甲基和亚甲基团。在更早的时候 研究发现，硫化假单胞菌在低产量下引入了一种羟基 关于双氢青蒿素的N-苯基脲的C-14甲基。 当双氢青蒿素的乙醚蒿醚被用作 一种具有相同真菌的底物两种羟化衍生物 分离的14-羟基乙醚和9-羟基乙醚。产量是 比从N-苯基氨基甲酸乙酯得到的 双氢青蒿素。制备的几种衍生物的体外研究 数据显示，它们的活性与乙醚大致相同。工作开始了 放大这些反应的进展，以便制备更大的 在小鼠身上进行试验的化合物的数量。

TheThe formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to develop resistance to new drugs, have stimulated interest in using combinations of drugs for treating this disease, which claims more than a million lives a year. Although strains of P. falciparum have become resistant to many drugs, no strains have thus far become resistant to derivatives of artemisinin. Artemisinin derivatives are thought to damage the parasite's membranes, while quinine or mefloquine inhibit dihydrofolate reductase. Thus, the parasite has to mutate at a different locus to become resistant to artemisinin. A large number of derivatives (esters and ethers of dihydroartemisinin) have been prepared in China and the United States and shown to be active against P. falciparum. For additional structure- activity studies, we wanted to introduce a new functional group into the molecule, without destroying the peroxide necessary for its antimalarial activity. We have investigated the ability of the fungus Beauveria sulfurescens to introduce hydroxy groups on unactivated methyl, methylene and methine groups in artemisinin derivatives. In an earlier study we found that B. sulfurescens introduced a hydroxy in low yield on the C-14 methyl of the N-phenylurethan of the dihydroartemisinin. When arteether, the ethyl ether of dihydroartemisinin, was employed as a substrate with the same fungus two hydroxylated derivatives were isolated, 14-hydroxyarteether and 9~-hydroxyarteether. The yields were greater than that obtained from the N-phenylurethane of dihydroartemisinin. In vitro studies of several derivatives prepared to date show them to be approximately as active as arteether. Work is in progress on scaling up these reactions, so as to prepare larger quantities of the compounds for testing in mice.