Many marine imidazole alkaloids such as clathridine 1, Naamidines (2-4), pyronaamidine 5 and isonaamidines (6, 7) have (1-methyl-2,5-dioxo-1,2,5H-imidazolin-4-yl) amino (MDA) moiety, which seems to be important for their antitumor and antifungal activities. We examined the dehydrative condensation of parabanic acid derivative with primary amines, and found an efficient and regioselective method for introduction of MDA by using 1-methyl-3-trimethylsilylimidazolidinetrione (9). The condensing agent 9 could be prepared from 1-methylparabanic acid 8 in 58% isolated yield by treatment with TMS_2NH. The reagent 9 gave regioselectively the desired condensation products 10 in 58-98% yields by only stirring with various primary amines in refluxing CHCl_3. Total syntheses of 1, 5, 6 and 7 were successfully achieved by applying the present method to the corresponding 2-aminoimidazole derivatives, prechlathridine A (12), naamine C (23), 33 and isonaamine A (34). Several synthesized compounds containing the MDA group were evaluated their antitumor activity, and some of them showed significant cytotoxicity against a wide variety of human tumor cells.
