Totalsynthese des mikrobiellen Naturstoffs Collinolacton aus Streptomyces sp. und Darstellung ausgewählter Derivate für biologische Untersuchungen

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The new secondary metabolite collinolactone was isolated from Streptomyces sp. by Grond et al. and features a rather unusual tricyclic core structure, consisting of a central ten-membered ring with anellated six- and seven-membered lactone moieties. Derivates of the natural product show a remarkable cytostatic activity and lead to formation of monoastral spindles in mitosis. The aim of this project is the first stereoselective total synthesis with formation of the ten-membered ring as central scientific challenge. Similar structures have so far not been prepared, thus, new synthetic routes have to be tested, e.g. an olefin metathesis for closure of the strained ten-membered ring.Altogether, an efficient, 19-step synthesis shall be elaborated which also allows for preparation of isotope-labeled biosynthetic precursors for feeding experiments as well as structure analogs of collinolactone. Thus, the first total synthesis of this natural product will also lead to elucidation of its biosynthesis, its structure-activity-relationships and its binding site. Together with collaboration partners, a complete understanding of collinolactone and its biologic potential shall thus be gained.