Total synthesis of novel polycyclic bioactive indole alkaloids

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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.