【作者】 刘新宇；

【导师】 吴劲昌；

【作者基本信息】 吉林大学 ， 有机化学， 2010， 硕士

【摘要】 构象限制核苷是近年来核苷化学中的研究热点,很多构象限制核苷被发现具有抗病毒和抗肿瘤的活性,同时它还被嵌入到“反义寡核苷酸”中用于基因治疗中。叠氮和炔参与的1,3偶极环加成反应是构建环体系的有效方法,本文目的在于开发分子内的叠氮和炔参与的1,3偶极环加成反应构建三氮唑修饰的3′,5′-并环构象限制核苷合成方法,并对所合成的目标产物的结构和构象进行研究为进一步的生物活性测试奠定基础。本文应用在核苷中先引入叠氮基再引入炔丙基的策略合成了九个脱氧核糖核苷和核糖核苷的叠氮和炔丙基双修饰的环合前体,应用分子内的叠氮和炔参与的1,3偶极环加成反应得到四个三氮唑修饰3′,5′-并环构象限制脱氧核糖核苷并成功将它们的4-羰基转化为氨基得到相应构象限制胞苷。对所有关键中间体和目标产物进行了详细的结构表征,对其中一个目标产物进行了晶体衍射,并进行了构象分析。更多还原

【Abstract】 Conformation restricted nucleosides extracted more attention of in recent years. They are a class of modified nucleosides, which refers to the nucleoside through the chain structure of the carbon-carbon atoms or oxygen atoms or carbon and nitrogen atoms connected by the nucleoside analogues. This more complex structure of modified nucleosides on conformational regulation and a certain limitation, and generally has a certain rigidity, with a variety of different interactions between the enzyme with high selectivity. Many conformation restricted nucleosides have a good anti-virus and anti-tumor activities, which was also embedded in "antisense" oligonucleotides and RNA interference such as high efficiency and low toxicity in treatment. This paper describes an application of azide and alkyne 1,3-dipolar cycloaddition in synthesis of 3′,5′-fused nucleosides and 3,5′-cyclonucleosides. The structure of target compound was characterized by LC-MS, 1H NMR, 13C NMR and X crystal diffraction, and conformation of the nucleoside studied too.The first part of the dissertation is concern on the background of our research. conformation constrained nucleosides and their research progress are introduced firstly. Secondly, azide and alkyne 1,3-dipolar cycloaddition reactions, their progress and their applications in nucleoside chemistry are disscussed. On the basis of these two part of research we put forward our ideas: 1) Synthesis 3′,5′-fused nucleosides and 3,5′-cyleonucleosides via intramolecular azide and alkyne 1,3-dipolar cycloaddition reactions; 2) Compounds containing triazole moiety exhibit profound activites; 3) The dipole moment makes triazole form hydrogen bonds with organisms , dipole interactions and accumulating effects readily; 4) Triazole with high chemical and biological stability may improve the pharmacokinetic properties of the nucleosides.The second part describes design and synthsis of two category of 3′,5′-fused nucleosides and 3,5′-cyleonucleosides. The first class is deoxy ribose nucleosides, in this part synthsis of cyclo precursors via sulfonation and nucleophilic substitution were used to introduce an azido group on the nuclesides and selectively alkynlation on the hydroxyl or 3-N of nucleosides. After 1,3-dipolar cycloaddition reactions in refluxing toluene or xylene four different 3′,5′-fused nucleosides were abtained, they are cyclo product of 3′-β-azido-5′-propargyl,3′-α- azido -5′- propargyl,3′-β- propargyl -5′- azido, 3′-α- propargyl -5′- azido thynidine. In the synthetic attamption of 3,5′-cyclothymidine we got cyclo precursor but the cycloaddition reaction did not carry out, and the cause of the result are disscussed thorogoughly. The second class is ribose nuclesides, similarly synthsis routes were adopted and all the cyclo precursors were synthesized, but cycloaddtions did not work either. Consulting the reason may be the 2′-substitiution make the conformation of the nucleosides quite different with the deoxy ones, it makes azido group and alkynyl too far to react with each other. At last the structure of target compounds were characterized thoroghly and refer to the literuture we concluded that it is 1,5-cycloaddition reactions in the synthesis. The conformation of one product was studied based on its crystal diffraction data. It is an N-type nucleoside with sugar moiety adopts an conformation between 2E and 23T .更多还原