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.