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

<p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>I. Bergman J, Wahlstrom N, Yudina L, Tholander J, Lidgren G (2002). "Synthesis of indolocarbazole quinones; potent aryl hydrocarbon receptor ligands." Terahedron 58: 1443-52 </p><p>II. Bergander L, Wahlstrom N, Alsberg T, Bergman J, Rannug A, Rannug U (2003). "Characterization of in vitro metabolites of the aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole by liquid chromatography-mass spectrometry and NMR. " Drug Metab Dispos 31(2): 233-41 <br><a href="https://pubmed.ncbi.nlm.nih.gov/12527705">https://pubmed.ncbi.nlm.nih.gov/12527705</a><br><br></p><p>III. Wahlstrom N, Stensland B, Bergman J (2004). "Synthesis of 2,3-diindolylmethanes and substituted indolo[3,2-b]carbazoles." Synthesis 1187-94 </p><p>IV. Wahlstrom N, Romero I, Bergman J (2004). "Synthesis of metabolites of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole." Eur J Org Chem 2593-2602 </p><p>V. Wahlstrom N, Bergman J (2004). "Synthesis of 2,3-biindolyls and indolo[3,2-a]carbazoles." Tetrahedron Letters (Accepted) </p><p>VI. Wahlstrom N, Stensland B, Bergman J (2004). "Synthesis of the marine alkaloid caulersin." Tetrahedron 2147-53 </p>