Total synthesis of novel polycyclic bioactive indole alkaloids

以药物发现过程为重点，北里研究所正在使用尖端、独特的筛选技术，从微生物代谢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，如新型多环吲哚生物碱、新恶灵和羟基异构体。新恶灵是从我所从日本曲霉FG-551中分离得到的。它是一类新的具有生物活性的吲哚生物碱的成员，其特征是具有独特的吲哚螺胺骨架。它与微管蛋白结合，从而抑制微管蛋白聚合。我们开发了一种简明的立体选择性合成吲哚螺胺骨架的方法，通过从呋喃吲哚到二胺的转氨化，然后在钨酸盐的催化下氧化成硝酮，该硝酮很容易环合成新奥沙林的吲哚螺胺骨架。从我们的天然产物库中提取的羟基安非他明最近被发现是一种有效的抗疟疾药物。它是一种吲哚生物碱，由一个6，8环系统组成，其中包括一个不稳定的正胺骨架。通过Staudinger/Aza-Wittig/分子内烷基化/分子内Mannich级联反应，以及由非对映选择性Michael反应和吲哚非对映选择性烷基化产生的两个立体中心，我们开发了第一个全合成羟基胺的策略，其特征是构建了6，8个环系，其中包含氨基部分。

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.