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: 6432086
• 负责人: Herman 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/6432086
• 关键词: antimalarial agents; autoradiography; chemical structure function; chemical substitution; drug design /synthesis /production; drug interactions; molecular asymmetry; nerve /myelin protein; neurotoxicology; nuclear magnetic resonance spectroscopy; sesquiterpenes; stereochemistry

Two series of N-substitutited 11-azaartemisinins were prepared and a new synthesis of 10b-alkyldeoxoartemisinis was developed. Many of the compounds were four or seven times more active in vitro against drug resistant strains of Plasmodium falciparum than the lead compound artemisinin. The first series involved a base catalyzed addition of olefins conjugated with a variety of electron withdrawing groups to 11-azaartemisinin. The second involved a dimethylaminopyridine catalyzed addition of terminal acetylenes conjugated to electron withdrawing groups to 11-azaartemisinin. The new synthesis of 10b-alkyldeoxoartemisinins from artemisinin was also developed. The synthesis involves redution of artemisinin by diisobutyl aluminum hydride followed by acetylation. The latter acetyl derivative was treated with titanium tetrachloride and a series of trimethylsiloxyl enol ethers to produce a series of 10b-alkyldeoxoartemisinins. The antimalarial activities of all new compounds were determined. A third series of compounds were prepared by acid catlyzed Michael additions to artemisitene. The compounds were four to seven times more active than artemisinin.

制备了两个n取代的11-青蒿素系列，并开发了一种新的10b-烷基脱氧青蒿素合成方法。许多化合物在体外对恶性疟原虫耐药菌株的活性是主要化合物青蒿素的4到7倍。第一个系列涉及一个碱催化加成烯烃与各种吸电子基团共轭到11-阿扎尔霉素。第二种方法是二甲氨基吡啶催化将末端乙炔偶联到吸电子基团上加成到11-阿扎霉素上。以青蒿素为原料合成了10b-烷基脱氧青蒿素。该合成包括用二异丁基氢化铝还原青蒿素，然后乙酰化。后一乙酰基衍生物经四氯化钛和一系列三甲基硅氧基烯醇醚处理，制得一系列10b-烷基脱氧青蒿素。测定了所有新化合物的抗疟活性。在青蒿素的基础上，通过酸催化合成了第三个系列化合物。这些化合物的活性是青蒿素的4到7倍。