Synthesis of NK109, an anticancer benzo[c]phenanthridine alkaloid

A total synthesis of NK109 (7-hydroxy-8-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phenanthridinium hydrogensulfate dihydrate), an anticancer benzo[c]phenanthridine alkaloid, is reported. The primary structure of this compound was erroneously communicated in 1973 as fagaridine (from Fagara xanthoxyloides) which is the 8-hydroxy regioisomer. NK109 has not yet been isolated from a natural source and therefore can only be obtained by synthesis. To study a wide variety of analogues, we decided to use a synthetic route via substituted benzylamine 5, which was obtained from the appropriate benzaldehyde and naphthylamine units. The benzo[c]phenanthridine ring was constructed by radical cyclization with tri-n-octyltin hydride and 2,2'-azobis(2-methylbutyronitrile), followed by oxidative aromatization with MnO2. The resulting benzo[c]phenanthridine 6 was successfully methylated with methyl 2-nitrobenzenesulfonate. After deprotection of the benzyl group and subsequent hydration, NK109 was obtained. All reactions were performed under normal conditions. Purification was achieved only by recrystallization to;give an overall yield of 40%.