偕二氟亚甲基苦马豆素类似物的设计与合成

Design and Synthesis of Gem-Difluoromethylenated Analogues of Swainonine

通过在天然苦马豆素的C8位引入二氟亚甲基并进行扩环改造,设计出了偕二氟亚甲基苦马豆素类似物1和2。在目标分子的合成中,经由R-叔丁基亚磺酰亚胺与二氟溴乙酸乙酯锌试剂的Reformatskii反应以及在叔丁醇钾作用下的氨基分子内亲核取代等反应构建了哌啶环,随后通过Grubbs二代催化剂催化下的烯烃关环复分解反应构建了目标分子的母环结构。结果表明:该合成路线具有氟修饰位点可控、较高的非对映选择性、高效构建双环的特点。所设计的分子具有潜在的抗肿瘤活性,并能为苦马豆素构效关系的研究提供帮助。

The gem-difluoromethylenated Swainonine analogues No.1 and No.2 were designed via a introduction of difluoromethylene group into the structure of Swainonine. The piperidine ring was synthesized throughReformatskii reaction between zinc bromodifluoroacetate with（R）-t-butyl sulfonimide and intermolecularSN2-amine replacement in the presence of potassium t-butylate. Then,the mother structure of the targetmolecules was constructed via ring-closing metathesis reaction of the resulting diene catalyzed by Grubbs＇ IIcatalyst. The synthetic route had the characteristics of controllable fluorine modified-sites,relatively highdiastereoselectivity and efficient construction of double rings. The designed molecule has potential anti-tumor activity and could be helpful for the research of study structure-activity relationship of swainonine.