Total synthesis of novel polycyclic bioactive indole alkaloids

北里研究所专注于药物发现过程，使用尖端的独特筛选技术从微生物代谢产物中发现有用的生物活性天然产物。这些新的天然产物具有独特的结构和诱人的生物活性，如新的多环吲哚生物碱、新恶啉和羟基罂粟碱。它是一类新的生物活性吲哚生物碱的成员，其特征在于独特的吲哚啉螺缩醛骨架。它与微管蛋白结合，导致抑制微管蛋白聚合。我们已经开发了一个简洁的立体选择性合成吲哚啉螺缩醛骨架，从furoindoline转氨二胺，然后由钨酸盐催化氧化的硝酮，它很容易环化吲哚啉螺缩醛骨架neoxaline.Hydroxyapparicine，从我们的天然产物库，最近被发现是一个有效的抗疟疾剂。它是一种吲哚生物碱，由6，8环系统组成，包括不稳定的假缩醛胺骨架。我们首次采用Staudinger/Aza-wittig/分子内烷基化/分子内Mannich级联反应，通过非对映选择性Michael反应和吲哚的非对映选择性烷基化，沿着两个立体中心，构建了含假缩醛胺结构的6、8环体系，从而实现了羟基罂粟碱的全合成。

With a focus on the drug discovery process, the Kitasato Institute is using cutting-edge, unique screening techniques to discover useful bioactive natural products from microbial metabolites. These novel natural products have distinctive structures and attractive bioactivities, such as novel polycyclic indole alkaloids, neoxaline and hydroxyapparicine.Neoxaline was isolated from Aspergillus japonicus Fg-551 in our institute. It is a member of a novel class of biologically active indole alkaloids characterized by a unique indoline spiroaminal framework. It binds to tubulin, resulting in inhibition of tubulin polymerization. We have developed a concise stereoselective synthesis of the indoline spiroaminal framework, by transamination from furoindoline to diaminal, followed by tungstate-catalyzed oxidation to the nitrone, which easily cyclizes to the indoline spiroaminal framework of neoxaline.Hydroxyapparicine, from our natural product library, was recently discovered to be a potent antimalarial agent. It is an indole alkaloid consisting of a 6, 8 ring system that includes an unstable Psude-aminal skeleton. We have developed the first total synthesis of hydroxyapparicine using a strategy featuring the construction of 6, 8 ring systems containing the Psude-aminal moiety using a Staudinger/Aza-wittig/intramolecular alkylation/intramolecular Mannich cascade reaction, along with two stereo-centers, produced by diastereoselective Michael reaction and diastereoselective alkylation of indole.