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1,5-自由基转移反应合成螺环核苷—合成与结构研究

1, 5-Radical Translocation Approach to the Spironucleosides-Synthesis and Structure Study

【作者】 党绍锋

【导师】 吴劲昌;

【作者基本信息】 吉林大学 , 有机化学, 2008, 博士

【摘要】 核苷类化合物是人们对抗病毒尤其是HIV病毒的首先药物,近年来研究发现一些构象限制的螺环修饰核苷具有较高的抗病毒活性。本论文首次将1, 5-自由基转移反应巧妙的引入到2′, 3′, 4′-螺环修饰核苷的合成中。对1, 5-自由基转移反应合成螺环修饰核苷的合成方法进行了研究,成功的合成了结构新颖的3′, 4′-螺环修饰核苷;研究了多种合成2′, 3′, 4′-螺环修饰核苷自由基转移前体的方法,发现了烯丙基溴或炔丙基溴选择性的单烷基化核苷糖环2′, 3′, 4′-酰胺的方法,丰富了修饰核苷的合成;并对所合成的螺环修饰核苷进行了结构表征,确认了螺环结构,且由表征结果可知,反应有一定的立体选择性。论文的第一章介绍了课题的研究背景。论文的第二章叙述了螺环修饰核苷的研究进展,以及合成2′, 3′, 4′-螺环修饰核苷的常用方法,并综述了1, 5-自由基转移反应及其在合成螺环化合物中的应用。在此基础上设计了利用1, 5-自由基转移反应合成2′, 3′, 4′-螺环修饰核苷。第三章探讨了1, 5-自由基转移反应在合成2′, 3′, 4′-螺环修饰核苷类化合物中的应用。合成出3′, 4′-螺环修饰核苷,并对其结构进行了表征。同时在合成螺环修饰核苷的过程中发现了烯丙基溴或炔丙基溴选择性的单烷基化核苷糖环2′, 3′, 4′-酰胺的方法。利用1, 5-自由基转移反应合成2′, 3′, 4′-螺环修饰核苷的合成设计以及合成方法的研究,对修饰核苷的合成具有很好的参考和使用价值;得到的3′, 4′-螺环修饰核苷为后续开展核苷构象研究,进一步筛选具有抗病毒活性的核苷药物打下了基础。

【Abstract】 Chapter one provides the background and significance of the thesis. Diseases of cancer and virus infection are life threatening with unmet needs in therapeutical treatment until now. With the recent advances in understanding molecular biology of the diseases, researches for new drugs with more potency and lower toxicity have been made impressive progresses. In particular, nucleoside derived drugs have played an essential role in therapy against epidemical diseases caused by virus infection. The development of methodologies for nucleoside synthesis and pharmacological study of the modified nucleosides have continueously been an important and promising area in drug discovery arena.Chapter two reviews the research progresses and the synthetic methods of spironucleosides in the literature. Introduction of cascade of radical translocation/cyclization reactions and methods for the preparation of spiro-compounds including a few examples of spironucleosides are summarized. Finally, we outline the ideas behind our interests of spironucleoside in synthesis and biological study.Most of nucleoside drugs on the market or drug candidates in clinical phases structurally belong to a category of modified nucleosides on sugar moiety. However, the modifications combined with spiro ring are rare, presumably due to the difficulty in synthesis. The spiro ring in spironucleosides shall have notable effects on the conformation of furanose and will produce profound impact toward their pharmacological profile. Some stimulate results from biological tests of spironucleoside have been revealed. Several synthetic methods have been developed for the preparation of these nucleoside analogues, including: 1) radical reaction; 2) nucleophilic addition or nucleophilic substitution reaction; 3) glycosididation between ribose and nucleobase; 4) condensation/polymerization reaction. Among those methods, 1, 5-radical translocation reaction which has extensive application in the synthesis of natural products with unusual structural features has not been explored in the synthesis of 2′, 3′, 4′-spironucleosides. Therefore, the research work in this thesis is to synthesize those spironucleosides and to study their molecular structure and biological activity.Chapter three deals with our research on the development of a new method for the preparation of 2′, 3′, 4′-spironucleosides via cascade of 1, 5-radical translocation/cyclization reaction. Through intensive examination under different conditions (such as changing solvent, temperature, concentration, bases, ratio of radical precursor and radical initiator in radical reactions), we find a novel synthetic method for the construction of spironucleosides by cascade radical translocation cyclization of N-allyl-N-(2′-bromophenyl) amide of 5′-carboxylic nucleoside derivatives and of the N-propynyl analogues.Thus, proper 5′-carboxylic acids of hydroxyl protected nucleosides were coupled with 2-bromo- or 4-methoxy-2-bromoaniline followed by N-alkylation with allyl bromide or propynyl bromide to afford radical precursors. This general synthetic method was introduced by us the first time. The precursors were then treated with tri-n-butyltin hydride in the presence of 2, 2′-azo-bis-iso-butyronitrile as radical initiator to lead 5-exo-trig or 5-exo-dig cascade cyclization via of 1, 5-radical translocation reaction, forming the desired 4′-spironucleosides alone with amount of byproduct from direct cyclization of primary aryl radical and unsaturated bond.For expansion of the methodology described above for the synthesis 2′, 3′- spironucleosides, many attempts have been made with different radical precursors in our research. Unfortunately, we could not achieve any successful outcome so far. Appropriate radical precursors and proper reaction conditions for the synthesis of 2′and 3′spironucleosides need to be investigated in the future.The synthesized 4′-spironucleosides 3-42a and 3-42b were fully characterized by 1H NMR, 13C NMR, NOE, COSY and LC-MS. Compounds of 4′-spironucleosides 3-43, 3-44, 3′-spironucleosides 3-74 and byproducts 3-41 and 3-45 were characterized by 1H NMR, 13C NMR and LC-MS. The structures of spironucleosides, by-products and the intermediates have been elucidated based on analytical data.The biological tests of the spironucleosides are to be investigated in the near future.

  • 【网络出版投稿人】 吉林大学
  • 【网络出版年期】2008年 11期
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