Synthetic Studies on Antitumor Antibiotics Mitomycin C and its Congeners

点击翻译按钮获取中文摘要

Mitomycin C is currently used as chemotherapeutic agent for the treatment of cancer. FR900482 isolated by Fujisawa Pharmaceutical Co., Ltd also possesses parallel antitumore activity as well. We previously achieved total syntheses of both compounds in racemic form. These syntheses, however, is not practical enough to apply these for large-scale production. A main proposes of this research is development of practical and flexible synthetic routes, which would be applicable for mitomycin C, FR900482 and their congeners. After retrosynthetic analysis, we chose 8-membered ring compound as a key intermediate. For the construction of the 8-membered key intermediate, we initially tested intramolecular alkylation reaction between anion and epoxides. Since the intramolecular alkylation approach gave no successful results, we then investigated intramolecular 1,3-dipolar cycloaddition approach using nitrile oxides. Nitrile oxide cycloaddition of the model compounds which is lacking substituents on benzene ring afforded the desired 8-membered ring cycloadducts in reasonable yield. Unexpectedly, however, the substrate for FR900482 bearing appropriate substituents on benzene ring gave an undesired 9-membered ring compound due to changing the regiochemistry of cycloaddition reaction. After further investigations, it was found that cinnamate type substrate afforded the desired 8-membered ring product even with appropriate functionality on benzene ring. Further elaboration from the cycloadduct to FR900482 and its congeners is under investigation.