单萜吲哚生物碱Scholarisine A的合成研究

Scholarisine A, a representative member of the monoterpenoid indole alkaloid family, was first isolated from the leaves of Alstonia scholaris by Luo and co-workers in 2008. It comprises an unique and unprecedented scaffold containing a bridged lactone embedded in a complex cagelike skeleton. Picraline, a putative biosynthetic precursor of scholarisine A, has been reported to be a selectivitive inhibitor of SGLT2, which was shown by recent studies to have the potential to be used in the treatment of type-II diabetes; however, scholarisine A itself has no bioactivities reported so far. As our continuing efforts in the total syntheses of indole alkaloids, we herein wish to accomplish a concise total synthesis of scholarisine A, to explore efficient synthetic methods to construct the multi-ring system of this type of cagelike structure, and to search small molecule probes for drug discovery through chemical syntheses and structure-activity relationship (SAR) investigations. The highlights of our strategy include an anionic cyclization featuring a Michael addition to allyl 5-nitropent-2-ynoate moiety, a Lewis acid-promoted intramolecular addition to forge a lactone bridged ring, and applications of sequential 1,4-conjugate reduction and alkylation.

2008年昆明植物所罗等人从Alstonia scholaris的树叶中分离得到的Scholarisine A是单萜吲哚生物碱中具有代表性的分子。分子含有一个复杂独特的内酯桥环笼状结构，结构非常奇特。Scholarisine A的生源假说前体Picraline具有优异的生物活性，是SGLT2选择性的抑制剂，最近研究表明它可望用于治疗二型糖尿病，但到目前为止还没有Scholarisine A本身的生物活性方面的报道。作为我们在吲哚生物碱全合成这一领域的持续发展之一，我们拟针对Scholarisine A展开全合成研究，并探索构筑这类多环体系笼状结构化合物的通用合成方法，并期望通过相关化学合成和构效关系研究，发现有益于日后新药发现的小分子探针化合物。我们合成策略的主要特色包括：炔酸酯的Michael加成和Lewis酸催化的烯醇硅醚对缩醛的进攻构建内酯桥环体系；串联的1,4-还原/烷基化反应等。

2008年昆明植物所罗等人从Alstonia scholaris的树叶中分离得到的Scholarisine A是单萜吲哚生物碱中具有代表性的分子。分子含有一个复杂独特的内酯桥环笼状结构，结构非常奇特。Scholarisine A的生源假说前体Picraline具有优异的生物活性，是SGLT2选择性的抑制剂，最近研究表明它可望用于治疗二型糖尿病，但到目前为止还没有Scholarisine A本身的生物活性方面的报道。作为我们在吲哚生物碱全合成这一领域的持续发展之一，我们针对Scholarisine A及相关天然产物展开了合成研究，并探索构筑这类多环体系笼状结构的通用合成方法，并期望通过相关化学合成和构效关系研究，发现有益于日后新药发现的小分子探针化合物。虽然尚未完成Scholarisine A本身的全合成，但我们成功实现了同属一个家族、具有显著生物活性、结构复杂的吲哚生物碱Aspidophylline A的不对称全合成。