ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

不对称合成——结构、立体化学和核磁共振

• 批准号: 3754167
• 负责人: H ZIFFER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3754167
• 关键词: antimalarial agents; benzene; chemical addition; chemical structure function; chemical substitution; chemical synthesis; drug design /synthesis /production; erythrocytes; hydroxyl group; hydroxylation; molecular asymmetry; molecular polarity; nuclear magnetic resonance spectroscopy; sesquiterpenes; stereochemistry; stereoisomer; tritium

In earlier work we developed a method for preparing 14-[2H]-arteether and have now employed that reaction sequence to prepare 14-[3H]-arteether. The 3H labeled arteether was used to study the mechanism of action of this group of antimalarial drugs. Infected and uninfected red blood cells were treated with labeled arteether, dihydroartemisinin and a third drug that also contains the same endoperoxide grouping. The same six proteins were found to react in infected cells, whereas none of the proteins in the uninfected red cells reacted with these compounds nor with a control, [3H]- desoxyarteether. These findings make it possible to identify, purify and study the structure and function of the reactive proteins. Diastereofacial additions of primary alcohols to the carbon-carbon double bond of anhydrodihydroartemisinin, catalyzed by triphenyl-phosphine hydrobromide, were employed to prepare a series of 11- epidihydroartemisinin derivatives. These additions enabled us to prepare previously unknown epimeric arteethers. The antimalarial activity of 11- epi-dihydroartemisinin was examined and found to be half as active as the isomer with the natural configuration at C-11. A study of minor reaction products as a function of the number of equivalents of alcohol employed, provided invaluable information on the mechanism of the reaction and on the stereochemistry of the reaction using Polarized c-Frontier Molecular Orbital Theory. Our study of the regio- and stereo-selectivity of Beauveria sulfurescens mediated hydroxylation of 1,4-disubstituted benzenes have shown that the beta-carbon of the alkyl side chain is selectively hydroxylated.

在早期的工作中，我们开发了一种制备14-[2 H]-蒿乙醚的方法， 现已采用该反应顺序制备14-[3 H]-蒿乙醚。 用~ 3 H标记的蒿乙醚研究其作用机制。 这组抗疟疾药物。 感染和未感染的红血 用标记的蒿乙醚、双氢青蒿素和第三种药物处理细胞， 也含有相同内过氧化物基团的药物。 相同的六 发现蛋白质在感染的细胞中发生反应，而没有一种蛋白质在感染的细胞中发生反应。 未感染红细胞中的蛋白质与这些化合物反应， 与对照，[3 H]-脱氧蒿乙醚。 这些发现使得 鉴定、纯化和研究活性物质的结构和功能， proteins. 伯醇对碳-碳双链的非立体加成 三苯基膦催化脱水二氢青蒿素的键 氢溴酸盐，用于制备一系列11- 表二氢青蒿素衍生物。 这些补充使我们能够准备 以前未知的差向异构蒿乙醚。 11- 12 - 13的抗疟活性 对表二氢青蒿素进行了检查，发现其活性为 在C-11位具有天然构型的异构体。 轻微反应的研究 产物作为所用醇当量数的函数， 提供了关于反应机制和 使用极化c-前线分子的反应的立体化学 轨道理论 硫化白僵菌区域和立体选择性的研究 介导的1，4-二取代苯的羟基化已经表明， 烷基侧链的β-碳被选择性羟基化。