Vintonyak Viktor V, Kunze Brigitte, Sasse Florenz, Maier Martin E
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Chemistry. 2008;14(35):11132-40. doi: 10.1002/chem.200801398.
Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.
通过Mitsunobu反应将新Pelolide的核心结构内酯16 a与含恶唑的侧链23结合，得到细胞毒性天然产物新Pelolide（2）。侧链23由恶唑酮24通过相应的三氟甲磺酸酯制备。制备23的关键步骤是Sonogashira偶联、烯胺烷基化和Still-Gennari Horner-Emmons反应。通过在烯丙基化步骤中改变Leighton试剂，制备了内酯16 a的11-差向异构体化合物50。这导致了11-表新Pelolide 51。新Pelolide的5-差向异构体化合物52可从Prins环化的次要异构体获得。此外，还制备了一系列侧链有修饰的类似物。所有衍生物都检测了对哺乳动物细胞培养物的毒性作用以及对牛心亚线粒体颗粒中NADH氧化的抑制作用。内酯部分的修饰在一定程度上是可以耐受的。另一方面，缩短恶唑与内酯之间的距离会导致活性显著下降。具有额外双键的类似物65与新Pelolide本身具有同等或更高的活性。
