Synthesis of indoles, bisindoles and indolocarbazoles : High affinity aryl hydrocarbon receptor ligands

Abstract: This thesis deals with the synthesis and reactions of indoles, bisindoles, indolocarbazoles and their derivatives. New methods for ring formation of planar, heterocyclic quinones, with the indolo[3,2b]carbazole or indolo[2,3-b]carbazole structures are described. The synthesis of indolo[3,2b]carbazole-6,12-dione has been performed via ring oxidations or with two novel ring closing procedures. The corresponding indolo[2,3-b]carbazole-6,12-dione has been prepared in a related ring closing process with trifluoroacetic anhydride as the principal reagent. Five metabolites formed from the high affinity Ahr ligand, indolo[3,2-blcarbazole6carboxaldehyde have been identified. The precursors for their synthesis, the appropiate 2,3'bisindolylketones, have been prepared in a Lewis acid mediated acylation involving different indoles and indolyl-2-carbonyl chlorides. Synthesis of the metabolites proved the assigned structures as 2-hydroxy-, 8-hydroxy-, 2,10-dihydroxy-, 4,8-dihydroxy- and 2,8dihydroxyindolo[3,2-b]carbazole-6-carboxaldehydes. The corresponding hydroxylated acids and 6-unsubstituted indolo[3,2-b]carbazoles have also been prepared. 2Hydroxyindolo[3,2b]carbazole-6-carboxaldehyde has also been sulfated with pyridine-sulfur trioxide and isolated as the barium salt. The Vilsmeier reaction was first used to prepare highly activated 2,3'-biindolyls in triflic anhydride mediated couplings between substituted oxindoles and methyl. 5,6dimethoxyindole-2carboxylate. One of these 2,3'-biindolyls served as starting material in the synthesis of 2,3dihydroxyindolo[3,2-a]carbazole, a precursor to the marine sulfamate ancorinazole. Secondly, a Vilsmeier reagent was utilized in the short three step synthesis of the marine bisindolotropolone alkaloid caulersin, the structure of which has also been confirmed by X-ray crystallography.