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Studies towards the Synthesis of the Hypermodified Nucleoside Isolated from Mammalian Transfer Ribonucleic Acids and Its Isotopically Labelled Compounds.

从哺乳动物转移核糖核酸中分离的超修饰核苷及其同位素标记化合物的合成研究。

基本信息

批准号：
03670997
负责人：
ITAYA Taisuke
金额：
$ 1.34万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

The synthesis of the title compounds involves the Witting reaction or the Heck reaction, and transformation of the 1,2-diol compound to the cyclic carbonate, as the key steps. Although the Witting reaction using (R)-[2-carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) had not afforded the desired product at the nucleoside level, we obtained the key intermediate by employing 7- formyl-3-[2,3,5-tri-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]wye and the inner salt 2 derived from 1. We also demonstrated that the product obtained in the Wittig reaction between 2 and piperonal was optically pure. For the synthesis of compounds labelled with an isotope, several phosphonium salts (type 2) differently protected at the amino group were synthesized. Among them benzyloxycarbonyl and tert-butoxycarbonyl compounds gave positive results in the Wittig reaction with piperonal; the former was better in view of the yield. On the other hand N-(tert-butoxycarbonyl)vinylglycine was better than the benzyloxycarbonyl compound for the Heck reaction with 1-benzyl- 7-iodowye. Thus we established two stereoselective methods of preparing optically active (E)-(2-arylvinyl)glycine derivatives.It was necessary for us to elucidate the mechanism of the formation of the cyclic carbonates in the reaction of 1,2-glycols and oxalyl chloride for improvement of the yield of the target nucleosides. We then studied the reactions of oxalyl chloride with various 1,2- glycols; the results allow us to explain the formation of the carbonates in terms of stereoelectronically controlled cleavage of the tetrahedral intermediates. According to the proposed mechanism we may have a chance of finding how to prepare exclusively the carbonates or the oxalates, whichever we want. Further investigation along this line is under progress.

标题化合物的合成以Witting反应或Heck反应为关键步骤，1,2-二醇化合物转化为环状碳酸盐。虽然使用(R)-[2-羧基-2-[（甲氧基羰基）氨基]乙基]三苯基氯化磷(1)的Witting反应在核苷水平上不能得到所需的产物，但我们使用7-甲酰基-3-[2,3,5-三- o -（叔丁基二甲基硅基）- β - d -核呋喃基]wye和由1衍生的内盐2获得了关键中间体。我们还证明了2和胡椒醛之间的Wittig反应得到的产物是光学纯的。为了合成带有同位素标记的化合物，合成了几种在氨基上受到不同保护的磷盐（2型）。其中苯氧羰基和叔丁氧羰基化合物在与胡椒醛的Wittig反应中有阳性反应；就产量而言，前者较好。另一方面，N-（叔丁基羰基）乙烯基甘氨酸与1-苄基- 7-碘醚的Heck反应优于苯氧羰基化合物。因此，我们建立了两种立体选择性制备光学活性(E)-（2-芳基乙烯基）甘氨酸衍生物的方法。为了提高目标核苷的产率，有必要阐明1,2-二醇与草酰氯反应中环状碳酸盐的形成机理。然后研究了草酰氯与各种1,2-二醇的反应；这些结果使我们能够从立体电子控制的四面体中间体解理的角度来解释碳酸盐的形成。根据提出的机制，我们可能有机会找到如何只制备碳酸盐或草酸盐，无论我们想要什么。这方面的进一步调查正在进行中。