Synthetic studies of marine indole alkaloids and related systems

This thesis is mainly focussed oil the synthesis of marine indole alkaloids and related systems, many of which display interesting biological activities.

In the first part of this thesis we could establish and confirm the stucture of barettin and 8,9dihydrobarettin, isolated from the marine sponge Geodia baretti. The synthesis of barettin and 8,9dihydrobarettin was performed in this work, involving a highly functionalised arginine derivative. This arginine derivative was used in a peptide coupling with 6-bromotryptophan methyl ester, as in the case of 8,9-dihydrobarettin, or as a phosphonate derivative in a Homer-Wadsworth-Emmons reaction with 6-bromoindole-3carboxaldehyde, as in the key step in the synthesis of barettin. Both barettin and 8,9dihydrobarettin are highly efficient in inhibiting the settlement of cyprid larvae of the barnacle Balanus improvisus, which makes them especially interesting as potential antifouling agents. The synthesis of ail additional indole alkaloid, dipodazine (structurally related to barettin) is also described in this section.

Dipodazine has been isolated and characterised as a major metabolite from P. dipodomyis and was here synthesized via a stereoselective aldol condensation from Nprotected indole-3-carboxaldehyde and 1,4-diacetyl-2,5-piperazinedione ill the presence of caesium carbonate. Several analogues of dipodazine, together with a few barettin analogues have been prepared and tested for activity ill antifouling assays, results and relevance of which are discussed ill this thesis.

The second part of this thesis deals with the synthesis of the marine bis(indole) alkaloids rhopaladins A-D, isolated from the Okinawan marine tunicate Rhopalaea sp. The synthesis of the rhopaladins involved ail imidate based cyclisation with tryptophan esters as the key step. A short and efficient new synthesis of indole-3-carbonyl nitriles from indole-3carboxaldehydes and trimethylsilyl cyanide, followed by oxidation with DDQ is also described.

The last part of this thesis describes the synthetic approaches towards ail indole alkaloid isolated from a Caribbean sponge, Halichondria melanodocia Furthermore, an efficient method for preparation of certain carbazole derivatives, using indole and itaconic anhydride is described. Using this method, the 1-oxygenated carbazole alkaloid clausine E has been prepared in two steps.

List of scientific papers

I. Johnson AL, Bergman J, Sjogren M, Bohlin L (2004). Synthesis of barettin. Tetrahedron. 60: 961.
https://doi.org/10.1016/j.tet.2003.11.031

II. Johnson AL, Janosik T, Bergman J (2002). Synthesis of the diketopiperazine dipodazine. Arkivoc. 8: 57.

III. Janosik T, Johnson AL, Bergman J (2002). Synthesis of the marine alkaloids rhopaladinis A, B, C and D. Tetrahedron. 58: 2813.

IV. Johnson AL, Bergman J (2005). Synthetic approaches towards lactams isolated from the marine sponge Halichondria melanodocia. [Manuscript]