A VERSATILE AND EFFICIENT CONSTRUCTION OF THE 6H-PYRIDO[4,3-B]CARBAZOLE RING-SYSTEM - SYNTHESES OF THE ANTITUMOR ALKALOIDS ELLIPTICINE, 9-METHOXYELLIPTICINE, AND OLIVACINE AND THEIR ANALOGS

A general and efficient synthesis of the 6H-pyrido[4,3-b]carbazole ring system is described, in which the key steps are (1) regioselective acylation of a 2-lithio-1-(phenylsulfonyl)indole (14) with 3,4-pyridinedicarboxylic acid anhydride (10), (2) cyclization of the deprotected keto acid 17 to keto lactam 19 with acetic anhydride, and (3) the addition of methyllithium to give, after reduction of the intermediate diol 23 with sodium borohydride, the target ring system. In this fashion, ellipticine (1a), 9-methoxyellipticine (1b), and 9-hydroxyellipticine (1c) were synthesized in excellent overall yields from indole. The use of Superhydride, in place of 1 equiv of methyllithium, provided a synthesis of olivacine (2), and the use of phthalic anhydride in the sequence allowed for the preparation of 6,11-dimethylbenzo[b]carbazole (48). The overall yields of ellipticine (1a) (54%) and 9-methoxyellipticine (1b) (47%) in six steps from their respective indoles represent one of the most efficient syntheses of these antitumor alkaloids.