ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

在开发疟疾疫苗方面遇到的巨大问题，以及 恶性疟原虫对新药产生抗药性的能力 激发了使用药物组合治疗这种疾病的兴趣 这种疾病每年夺走100多万人的生命。当前的一种药物 感兴趣的青蒿素是由中国调查人员从一 传统草药。双氢青蒿素的酯和醚 已由几个小组准备用于其结构活性研究 抗疟疾特性。这些都证明了过氧化桥是 药理作用所必需的。为了增加 分子的功能，我们研究了真菌的能力 硫化白僵菌在N-苯基上引入羟基 双氢青蒿素氨基甲酸酯。从这些产品中分离出两种产品 学习。一种通过(1)H，(13)C和2D核磁共振研究表明含有一个新的 羟基，以羟甲基的形式存在，并且仍然具有完整的 生物活性所需的过氧化基。的结构。 第二个产物也通过核磁共振进行了鉴定，发现它是 由过氧化基的重排形成的。各种衍生品 将对第一种化合物进行制备和活性测试 对抗脑型疟疾。

The formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to become resistant to new drugs, have stimulated interest in using combinations of drugs for treating this disease, which claims more than a million lives a year. One drug of current interest, artemisinin, was isolated by Chinese investigators from a traditional medicinal herb. Esters and ethers of dihydroartemisinin have been prepared by several groups for structure-activity studies of their antimalarial properties. These demonstrated that the peroxide bridge was required for pharmacological activity. In order to increase the functionality of the molecule, we investigated the ability of the fungus Beauveria sulfurescens to introduce a hydroxyl group into the N-phenyl urethane of dihydroartemisinin. Two products were isolated from these studies. One was shown by (1)H, (13)C and 2D nmr studies to contain a new hydroxyl group, present as a hydroxymethyl, and still had intact the peroxide group required for biological activity. The structure of the second product was also determined by nmr and it was found to have been formed by a rearrangement of the peroxide group. A variety of derivatives of the first compound will be prepared and tested for their activity against cerebral malaria.