A stereoselective synthesis of tilivalline and its analogs utilizing a new Mannich type intramolecular cyclization

Abstract

Tilivalline (1a), a metabolite isolated from Klebsiella pneumoniae var. oxytoca, belongs to a group of pyrrolo[2,1-c][1,4]benzodiazepines, a characteristic skeleton of anthramycin-type antitumor antibiotics. We have accomplished a completely stereoselective, efficient and convenient synthesis of la utilizing a new Mannich type intramolecular cyclization as a key step. Further, a computational chemical analysis clarified the effect of zinc chloride on the high stereoselectivity in the tilivalline synthesis. To aim both the extension of the scope of the new Mannich type intramolecular cyclization and the studies on the structure-biological activity relationship, we further extended the method to the synthesis of tilivalline derivatives and 2-(3'-indolyl)-1,4-benzodiazepines (50). Investigation on the cytotoxicity of la and its analogs has revealed that la shows the strong cytotoxicity toward mouse leukemia L 1210 cells and the replacement of the indole function of la with cyano one increases the cytotoxicity of la about 100 times (IC50=0.05 μg/ml).