生物活性导向的麦角碱的多样性合成

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 enantiospecific synthesis of (+)-cycloclavine would be accomplished by a late-stage Simmons-Smith cyclopropanation from A. The skeletal tetracyclic core segment of the ergot alkaloids B was also obtained from A, by the further ring-expanded reaction sequence, involved oxidation subsequent intra- molecular aldol condensation. The diversity-oriented syntheses of ergot alkaloids would be reached from B. The proposal also made a new route to the preparation of lysergic acid by aza-Prins cyclization of the alkynyl tosyl-iminium ion, and further Heck cross-coupling reaction and oxidation, which provided another efficient entry into the synthesis of structurally analogies of the ergot alkaloids. Thus the syntheses of 25 target molecules would be carried out smoothly. The examinations of biological and pharmacological properties,as well as the structure activity relationships will be go on for the synthetic ergot alkaloids, it is a fertile ground for chemists, one that is beginning to facilitate the development of new medicines and its candidates.

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。

麦角生物碱(ergot alkaloids)是由麦角菌属(claviceps)在多种禾本科植物产生的生物碱，活性显著结构多样复杂，麦角生物碱的药理功能主要有：治疗偏头疼、脑血管功能不全等疾病，麦角新碱及其它经结构改造的麦角生物碱衍生物已用于临床。医用麦角生物碱大多来自天然麦角生物碱经过结构修饰及化学合成，因而麦角生物碱合成研究历来很受重视。项目以生物活性为导向，发展简洁高效构筑麦角生物碱骨架的方法，再通过骨架进行多样性合成策略开展麦角生物碱的合成研究。我们发展了基于aza-Cope-Mannich反应构筑二氢吡咯环骨架和分子内Heck偶联或6-exo-trig自由基环化构筑3,4位绸合吲哚骨架的新策略完成了(±)-cycloclavine的形式合成，合成路线简洁，操作方便，产率高。以此为基础也探索了通过底物诱导的aza-Cope-Mannich反应进行不对称合成(+)-cycloclavine。麦角生物碱大都含有3,4-稠合的吲哚环骨架结构，传统的合成一般以4位带官能团的吲哚为原料，然而吲哚的4位反应活性相对较低，合成中很有挑战。我们采用了在合成的末期制备吲哚环的策略，有效解决了这一难题。从手性原料(R)-(+)苯基环氧乙烷开始，以分子内[3+2]环化反应构筑了3,4-稠合吲哚骨架为关键步骤，通过底物诱导完成了(-)-chanoclavine全合成。.项目也开展了麦角生物碱的多样性合成，多渠道保证制备麦角生物碱的新途径。例如，通过分子内aza-Cope-Mannich反应、[3+2]环加成反应、Diels-Alder反应、分子内的串联反应等经济有效的方法制备关键中间体，进而进行麦角生物碱的多样性合成。天然产物全合成是有机化学中最重要和最具创造性的研究方向之一，也是难度最大、最具挑战性的研究工作。通过简洁高效构筑麦角生物碱骨架再进行多样性合成策略开展麦角生物碱的全合成，拓展了麦角生物碱的研究范畴，也拓宽了生物学和医药学等研究的范畴。