Enantioselektive Totalsynthese, biologische Aktivität und Strukturvariation des antitumoralen Alkaloids (-)-Dibromphakellstatin aus dem Meeresschwamm Phakellia mauritiana

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.