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Zöllinger, Michael (2007): Enantioselektive Totalsynthese, biologische Aktivität und Strukturvariation des antitumoralen Alkaloids (-)-Dibromphakellstatin aus dem Meeresschwamm Phakellia mauritiana. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Pyrrole-imidazole alkaloids represent a unique family of natural products which are exclusively found in marine sponges, mainly the Agelasidae, Axinellidae, and Halichondridae families. The pyrrole-imidazole alkaloids are fascinating due to thier biogenetic relationship leading to a large, strucurally diverse family based on a common key metabolite, oroidin. Some of the pyrrole-imidazole alkaloids have interesting biological activities, e. g., potent antitumor or antibacterial activities. One of these chellenging alkaloids is dibromophakellstatin which was first isolated from Phakellia mauritiana. In this work an efficient five step synthesis of dibromophakellstatin is described providing the natural product in an overall yield of 10%. Based on a broad investigation of the reactivity of dipyrrolopyrazinone-type enamides, a novel three component imidazolidinone anellation was exploited as the key step of the total synthesis. With this findings the overall yield of the synthesis could increased up to 18%. Based on these results it was possible to develope the first enantioselective total synthesis of (-)-dibromophakellstatin in a chiral pool approach (10 steps, 3.5% overall yield). In a collaboration effort the antitumor activity of dibromophakellstatin was confirmed. It was found that only the natural enantiomer shows biological activity by an unknown mechanism. Encouraged by the biological activity of (-)-dibromophakellstatin, different cyclopropane variations of the tetracyclic phakellin- and isophakellin scaffolds were obtained by reaction of dichlorocarbene with tri- and bicyclic precursors. Some of these compounds werde found to have interesting new anti proliferative activities.