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: 3776276
• 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/3776276
• 关键词: Plasmodium falciparum; antimalarial agents; chemical structure function; chemical substitution; chemical synthesis; drug design /synthesis /production; drug resistance; fluorine; hydroxyl group; mass spectrometry; medicinal plants; microorganism culture; molecular asymmetry; molecular polarity; molecular rearrangement; nuclear magnetic resonance spectroscopy; plant extracts; sesquiterpenes; stereochemistry

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.

青蒿素1已作为一种先导化合物，用于开发新的抗结核药物