Synthetic Studies of the Pyrroloquinoline Nucleus of the Makaluvamine Alkaloids. Synthesis of the Topoisomerase II Inhibitor Makaluvamine D

A new synthesis of the pyrrolo[4, 3, 2-rfe]quinoline system characteristic of a class of marine alkaloids which includes the prianosins, discorhabdins, and other antineoplastic agents has been developed. The approach is exemplified in a total synthesis of makaluvamine D, a topoisomerase II inhibitor isolated from the sponge Zyzzya cf. marsailis. The route begins with a Fischer indole synthesis employing (2, 3-dimethoxyphenyl)hydrazine (29) and dihydrofuran, and the resulting tryptophol 32 is protected as its ditosylate 34. Nitration at C4 of the indole, followed by reduction and cyclization, affords the tricycle 41, which is oxidized to the iminoquinone 42 with eerie ammonium nitrate. Replacement of the C7 methoxy substituent of the pyrroloquinoline by tryptamine could only be effected via the salt 42 and, after cleavage of the N-tosyl group followed by treatment with trifluoroacetic acid, gives makaluvamine D (3), which was isolated as its trifluoroacetate 48. Exposure of iminoquinone 42 to sodium azide unexpectedly produced the fully unsaturated pyrroloquinoline 44.