Synthesis of indolocarbazoles, bisindoles and related sulfur containing systems

This thesis is focussed mainly on the synthesis and reactions of various indolocarbazoles, bisindoles and related sulfur containing systems, all possessing structural features present in many biologically active, natural or synthetic compounds.

In the first part, synthetic routes towards the planar, pentacyclic ring systems of indolo[2,3-c]earbazole and indolo[3,2-a]carbazole are described. The synthesis of the parent indolo[2,3-c]lcarbazole was accomplished via a palladium acetate mediated cyclization of 1,2bis(1H-indol-2yl)ethane which was also demonstrated to serve as an excellent precursor for the preparation of a variety -of cyclohept[1,2-b:5,4-b´]bisindoles A variety of indolo[3,2a]carbazoles were obtained conveniently starting from 2,3'-biindolyl via electrocyclic reactions, or the interaction of 2,3´-biindolyl with a masked N,N- dimethylaminoacetaldehyde. In an extension, it was shown that access to indolo[3,2- a]pyrrolo[3,4-c]carbazoles and analogues thereof can also be easily gained.

The second part of this thesis deals with the synthesis of the marine alkaloid hyrtiosin B, which was achieved utilizing an efficient and concise route involving acylation of indolozinc reagents derived from 5 -methoxyindole, or even better, 5-benzyloxyindole, as the key step.

In the final and major section, the chemistry and reactions of various sulfur containing indoles and bisindoles are discussed. Thionation reactions using elemental sulfur or P4S10 performed on e.g., indigo, isatin, or 3,3'-biindolyl were shown to give bisindoles featuring polysulfur bridges, or having unusual rings incorporating both sulfur and phosphorus. The first example of a thionated indigo derivative with an established structure, i.e. monothioindigo was isolated from the reaction of indigo with P4S10 in pyridine. The interaction of sulfur with 2,2´-biindolyl was found to produce a system with four indole moieties having a 12-membered central ring incorporating two S,S-linkages. This molecule was also demonstrated to undergo transformation into two different conformers on dissolution in warm strongly polar solvents. In addition, the elusive [1,2]dithiino[4,3-b:5,6-b']diindole was isolated as a N,N- dimethylacetamide solvate, the structure of which was rigorously confirmed by X-ray crystallography Moreover, the synthesis and reactions of pentathiepino[6,7-b]indoles were studied. Pentathiepino[6,7-b]indoles proved to be readily accessible via the reaction of 2-lithiated indoles with elemental sulfur. A modification of the conditions, ie. using of one equivalent of sulfur, permitted a simple route to indoline-2 thiones from indoles. In addition trimerization reactions of indoline-2-thione or oxindole were investigated, demonstrating that treatment of indoline-2-thione with p- toluenesulflanyl azide gives a cyclic trimeric product while the oxidation of oxindole with iodine produces an acyclic trimer.

List of scientific papers

I. Bergman J, Janosik T, Yudina L, Desarbre E, Lidgren G, Venemalm L (2000). "Reactions of 1,2-bis(1H-indol-2-yl)ethane: formation of indolo [2,3-c]carbazole and cyclohept[1,2-b:5,4-b]bisindole derivatives." Tetrahedron 56: 1911

II. Janosik T, Bergman J (1999). "Reactions of 2,3-biindolyl: synthesis of indolo[3,2-a]carbazoles." Tetrahedron 55: 2371

III. Bergaman J, Janosik T, Johnsson AL (1999). "Synthesis of hyrtiosin B, a bisindole alkaloid from the Okinawan marine sponge Hyrtios erecta." Synthesis 580

IV. Janosik T, Bergman J, Stensland B, stalhandske C (2002). "Thionation of bisindole derivatives with P4S10 or elemental sulfur." J Chem Soc Perkin Trans (In Print)

V. Janosik T, Bergman J, Romero I, Stensland B, Stalhandske C, Marques MMB, Santos MMM, Lobo AM, Prabhakar S, duarte MF, Florencio MH (2002). "Synthetic, spectroscopic, and X-ray crystallographic studies of [1,2,7,8]tetrathiacyclododecino[4,3-b:5,6-b:10,9-b:11,12-b]tetraindoles." (Submitted)

VI. Rewcastle GW, Janosik T, Bergman J (2001). "Reactions of 2-lithiated indoles with elemental sulfur. Formation of pentathiepino[6,7-b]indoles and indoline-2-thiones." Tetrahedron 57: 7185

VII. Janosik T, Bergman J (2002). "Oxidative coupling of indoline-2-thione or oxindole: formation of cyclic and acyclic indole trimers." (Manuscript)