ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

青蒿素1已成为开发新药物的先导化合物。 用于治疗恶性疟原虫耐药株的抗疟疾药物。 疟疾是传播最广的寄生虫病，约有2.7亿人感染。 全球范围内的人口，每年造成一两百万人死亡。许多 来自东南亚的恶性疟原虫菌株已经对这种 目前使用的毒品，并有可能蔓延到亚洲、非洲其他地区 以及中南美洲。我们首先使用了一种真菌白僵菌 硫化试剂在β-Arteether 2中引入羟基的努力 提高其治疗指标。羟基化化合物被用作 几种合成中的中间体。作为一些氟化类固醇， 前列腺素、核苷、胺等都是有价值的药物， 目前还没有已知的含氟青蒿素衍生物，我们使用的是羟基 以芳香醚为中间体制备含氟芳香醚。几个 含有羰基的青蒿素衍生物也被转化 变成了宝石般的二氟衍生物。所有含氟化合物均为 作为Arteether(计划用于临床测试)的活性物质 恶性疟原虫抗性克隆的研究。 考察现有立体化学对其的影响 抗疟疾活性，我们寻找了新的方法来改变 组1。通过制备脱水二氢青蒿素3来完成 双氢青蒿素4及其化学成分的测定。化合物3被转化为 与间氯过苯甲酸的KF络合物反应生成β-环氧化物5。 β-环氧化物被转化为α，β-，12β- 二氢青蒿素，6.化合物3被氧化成11α， 12α-二羟基二氢青蒿素7与四氧化三铯配伍。它也是 用作制备11-[~3H]-芳香醚的起始原料 16.用于准备16的推理序列也被用于 11-表氢青蒿素系列醚类化合物的合成 在这些研究中，发现了两个新的重排。它的结构和 重排产物的立体化学由一维和二维结构确定。 核磁共振研究和质谱学。

Artemisinin 1 has served as a lead compound in the development of new antimalarial drugs to treat resistant strains of Plasmodium falciparum. Malaria is the most widespread parasitic disease infecting some 270 million people worldwide and causing one to two million deaths per year. Many strains of P. falciparum from Southeast Asia have become resistant to the drugs currently used and threaten to spread to other area of Asia, Africa and Central and South America. We first employed a fungus Beauveria sulfurescens to introduce hydroxy groups into beta-arteether 2 in an effort to improve its therapeutic index. The hydroxylated compounds were used as intermediates in several syntheses. As a number of fluorinated steroids, prostaglandins, nucleosides, amines, etc. are valuable medicinals and since no fluorinated artemisinin derivatives were known, we used the hydroxy arteethers as intermediates to prepare fluorinated arteethers. Several artemisinin derivatives, containing carbonyl groups, were also transformed into geminal difluoro derivatives. All the fluorinated compounds were as active as arteether (which is scheduled for clinical testing) against resistant clones of P. falciparum. To examine the influence of the existing stereochemistry on its antimalarial activity, we sought new methods to alter the sterochemistry of groups in 1. That was done by preparing anhydrodihydroartemisinin 3 from dihydroartemisinin 4 and examining its chemistry. Compound 3 was converted into the beta-epoxide 5 with the KF-complex of m-chloroperbenzoic acid. The beta-epoxide was converted into an alpha,beta-, 12beta- dihydroxydihydroartemisinin, 6. Compound 3 was oxidized to 11alpha, 12alpha-dihydroxydihydroartemisinin 7 with osmium tetraoxide. It was also employed as a starting material for the preparation of 11-[3H]-arteether 16. The reastion sequence used to prepare 16 was also used in the synthesis of a series of 11-epidihydroartemisinin ethers, 8. In the course of these studies two new rearrangements were discovered. The structure and stereochemistry of the rearrangement products were determined by 1D and 2D- NMR studies and mass spectrometry.