Speradines和aspergillines的全合成研究

Speradines and aspergillines, isolated and identified from different fungal sources, are structurally related to alfa-cyclopiazonic acid (alfa-CPA). They are synthetic challenge due to they include a caged hexacyclic (6/5/6/5/5/5) heterocyclic ring system, 6-7 contiguous stereocenters. In addition, they exhibited the biological activity against tobacco mosaic virus and moderate cytotoxicity in several human cancer cell lines. They have attracted wide attentions from synthetic chemists. Inspired by their biosynthesis pathway, we plan to design and develop an elegant cationic (3+2) cascade cycloaddition to enable rapid construction of the tetracyclic system, and then achieve the total synthesis of speradines and aspergillines. Furthermore, we will explore the catalytic asymmetric (3+2) cycloaddition by using chiral acid to achieve the asymmetric total synthesis of speradines and aspergillines. The value of this research subject is that it enriches the chemistry of alkaloids total synthesis, and it has also potential applications in the lead compound discovering.

Speradines和aspergillines是从不同霉菌中分离得到的alfa-环匹阿尼酸类生物碱，它们不仅具有一个共同的6/5/6/5/5/5六环刚性笼状骨架，且具有6-7个连续手性中心，极具合成挑战性；生物活性测试显示它们具有抗烟草花叶病毒和细胞毒活性。这类化合物已经引起了合成化学家的广泛关注。受其生源合成途径的启发，我们拟设计发展新颖的碳正阳离子介导的[3+2]环加成反应，快速构建关键四环体系，从而实现天然产物α-CPA及相关天然产物speradines和aspergilines等的高效全合成；并探索手性酸催化的[3+2]环加成反应，最终实现上述分子的高效不对称合成。开展本课题的研究不仅对丰富生物碱的全合成研究具有学术意义，而且对相关先导化合物的发现具有潜在的实用价值。

α-环匹阿尼酸(α-cyclopiazonic acid, α-CPA)是1968年从青霉菌中分离得到的一种真菌毒素，speradines和aspergillines是从不同霉菌中分离得到高氧化态的-环匹阿尼酸类生物碱，它们不仅具有一个共同的6/5/6/5/5/5六环刚性笼状骨架，且具有6-7个连续手性中心，极具合成挑战性；生物活性测试显示它们具有抗烟草花叶病毒和细胞毒活性。这类化合物已经引起了合成化学家的广泛关注。我们根据该类天然产物的生源合成途径，设计发展了新颖的仿生碳正阳离子介导的[3+2]环加成反应，快速构建天然产物四环骨架，进而实现了环匹阿尼酸的7步仿生高效全合成及speradine C的首次全合成（10步）, 该路线也是目前已知环匹阿尼酸最短合成路线；并探索了该仿生[3+2]环加成反应的普适性和机理。值得一提的是，该仿生合成策略的发展和应用，极大地缩短了该类天然产物的合成步骤，大幅度提升了它们的合成效率。该研究不仅对丰富吲哚生物碱的全合成具有学术意义，而且对相关先导化合物的发现具有潜在的实用价值。