生物活性导向的麦角碱的多样性合成

项目名称： 生物活性导向的麦角碱的多样性合成

项目编号： No.21272098

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 曹小平

作者单位： 兰州大学

项目金额： 80万元

中文摘要： 麦角碱（Ergot alkaloids）是由麦角菌属(Claviceps)产生的一大类生物碱，生物活性好结构多样复杂，麦角新碱(Ergonovine)、麦角酰胺(Ergotamine)及其它经化学改造的麦角碱衍生物已用于临床。本项目以生物活性为导向，采用多样性合成策略开展麦角酸衍生物和麦角肽碱的全合成研究。首先通过底物诱导的aza-Cope-Mannich串联反应及分子内Heck偶联，或吲哚衍生物的亲核加成及Stille偶联构筑关键中间体A，从而完成(+)-Cycloclavine的全合成。以A进行开环-分子内aldol扩环合环制备麦角碱的母核四环骨架B，以此拓展目标分子的多样性合成，也将通过aza-Prins反应开辟制备麦角酸的新途径，多渠道保证了所设计的两类共25个麦角碱目标分子的全合成。项目也将对合成产物进行生物活性及构效关系的研究，以期筛选出具有临床应用前景的药物先导化合物。

中文关键词： 麦角生物碱；合成；cycloclavine；chanoclavine；

英文摘要： Ergot alkaloids are produced by the plant parasitic fungi, predominantly Claviceps. More than 40 ergot alkaloids have been isolated from ergot. The diverse structures of ergot alkaloids resulted in marked effects on their biological activity. Ergonovine, Ergotamine, and the ergot alkaloids derivatives exhibit a wide spectrum of therapeutic effect, provide to be useful remedies in modern medicine. They are widely used for the clinical treatment of several diseases. The structural similarities of ergot alkaloids with several neurotransmitters and thus wide-scale physiological influence make this a very interesting group of metabolites for the development of the medicines. Indeed large efforts are also made into finding better and more suitable derivatives, as well as economic ways of synthesizing them. The proposal (research project) focus on the total synthesis of two series of ergot alkaloids: lysergic acid derivatives and ergopeptines, based on the guidance of biological activity and diversity-oriented synthesis. Key features included the rapid construction of the advanced intermediate A through the substrate-induced stereospecific aza-Cope-Mannich tandem cyclization followed by intramolecular Heck cross-coupling reaction,or the nucleophilic addition of indo-alkynyl derivatives followed by Stille reaction. The

英文关键词： ergot alkaloids；synthesis；cycloclavine；chanoclavine；