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

Grond等人从Streptomyces sp.中分离出一种新的次级代谢物collinolactone，其核心结构为三环，由一个中心十元环和一个有突起的六元和七元内酯组成。天然产物的衍生物显示出显著的细胞抑制活性，并导致有丝分裂中单星纺锤体的形成。该项目的目的是第一个立体选择性全合成与形成的十元环为中心的科学挑战。到目前为止，还没有类似的结构被制备出来，因此，必须测试新的合成路线，例如，用烯烃复合法闭合应变的十元环。总的来说，一个高效的19步合成将被详细阐述，这也允许为喂养实验制备同位素标记的生物合成前体以及collololactone的结构类似物。因此，这一天然产物的首次全合成也将导致其生物合成、结构-活性关系和结合位点的阐明。与合作伙伴一起，全面了解collinolactone及其生物学潜力。

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.