A Noven Radical Ring-Enlargement Reaction : The Reaction Mechanism and the Medicinal Chemical Application

新型自由基扩环反应:反应机理及医药化学应用

基本信息

  • 批准号:
    11672095
  • 负责人:
  • 金额:
    $ 2.18万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2000
  • 项目状态:
    已结题

项目摘要

We developed a regio-and stereoselective method for introducing 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols using an intramolecular radical cyclization reaction with a dimethyl-or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or α-phenylselenoalkanols was subjected to the radical reaction with Bu_3SnH/AIBN, the selective introduction of both 1-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu_3SnH in the reaction system, via a 5-exo-cyclization intermediate or a 6-endo-cyclization intermediate, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether in the presence of (Bu_3Sn)_2, and then treating the resulting atom-transfer 5-exo-cyclization product with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical was trapped when the concentration of Bu_3SnH was high enough. At lower concentrations of Bu_3SnH and higher reaction temperatures, the 5-exo-cyclized radical rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical, which was then trapped with Bu_3SnH.The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state. This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of 4'-branched-chain sugar nucleosides as a nucleoside unit for antisense studies and also for potent antiviral nucleosides. C-glycosides trisphosphates as potent IP_3-receptor ligands were also synthesized using the radical reaction as the key step.
我们开发了一种区域和立体选择性方法,用于在卤代醇或α-苯基硒代烷醇中的羟基的β位引入1-羟乙基、2-羟乙基和乙烯基,使用分子内自由基环化反应,用二甲基或二苯基乙烯基甲硅烷基作为临时连接自由基受体系链(方案14)。因此,卤代醇或α-苯硒代烷醇的乙烯基硅醚与Bu_3SnH/AIBN进行自由基反应时,根据Bu_3SnH在反应体系中的浓度,可以分别通过5-外环化中间体或6-内环化中间体选择性地引入1-羟乙基和2-羟乙基,在Tamao氧化条件下处理环化产物进行氧化开环后。在(Bu_3Sn)_2存在下,通过光照射乙烯基硅醚,然后用氟离子处理原子转移5-外环化产物,也可以引入乙烯基。机理研究表明,当Bu_3SnH浓度足够高时,5-外环化自由基被捕获。在较低的Bu_3SnH浓度和较高的反应温度下,5-外环化自由基重排为更稳定的4-氧杂-3-硅杂环己基,然后被Bu_3SnH捕获,实验证明扩环重排是通过类似五价硅桥过渡态发生的.这种与乙烯基甲硅烷基系链的自由基反应已成功地应用于合成4 '-支链糖核苷,作为用于反义研究的核苷单元,也用于有效的抗病毒核苷。以自由基反应为关键步骤,合成了具有IP_3受体活性的三磷酸碳苷类配体。

项目成果

期刊论文数量(37)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
S.Shuto, et al.: "Mechanistic study of the ring-enlargement reaction of (3-oxa-2-silacyclopentyl) methyl radicals into 4-oxa-3-silacyclohexyl radicals. Evidence for a pentavalent silicon-bridging radical transition state in 1,2-rearrangement reactions of
S.Shuto 等人:“(3-oxa-2-silacyclopentyl) 甲基自由基成 4-oxa-3-silacyclohexyl 自由基的扩环反应的机理研究。五价硅桥自由基过渡态的证据
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    0
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R.D.Marwood, et al.: "Convergent synthesis of adenophostin A analogues via a base replacement strategy."Chem.Commun.. 219-220 (2000)
R.D.Marwood 等人:“通过碱基替换策略聚合合成腺苷磷蛋白 A 类似物。”Chem.Commun. 219-220 (2000)
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    0
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  • 通讯作者:
T.Kodama, et al.: "I'α-Branched-chain sugar pyrimidine ribonucleosides from uridine. The first conversion of a natural nucleoside into 1'-substituted ribonucleosides"Chem.Eur.J.. (in press).
T.Kodama 等人:“来自尿苷的 Iα-支链糖嘧啶核糖核苷。天然核苷首次转化为 1-取代核糖核苷”Chem.Eur.J.(印刷中)。
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
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  • 通讯作者:
S.Shuto, et al.: "Stereoselective synthesis of α-and β-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring."Tetrahedron Lett.. 41. 4151-4155 (2000)
S.Shuto 等人:“通过烯丙基甲硅烷基系链的自由基环化立体选择性合成 α-和 β-C-葡萄糖苷。通过改变吡喃糖环的构象控制立体选择性。”Tetrahedron Lett.. 41. 4151- 4155 (2000)
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  • 期刊:
  • 影响因子:
    0
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  • 通讯作者:
I.Sugimoto, et al.: "Kinetics of a novel 1,2-rearrangement reaction of β-silyl radicals"Synlett. 1766-1768 (1999)
I.Sugimoto 等人:“β-甲硅烷基自由基的新型 1,2-重排反应的动力学”Synlett,1766-1768 (1999)
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SHUTO Satoshi其他文献

SHUTO Satoshi的其他文献

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{{ truncateString('SHUTO Satoshi', 18)}}的其他基金

A Versatile Strategy for Developing Long-Acting Ligands by Ligand-Phospholipid Conjugation
通过配体-磷脂缀合开发长效配体的多功能策略
  • 批准号:
    16K15136
  • 财政年份:
    2016
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Medicinal chemical study by the three-dimensional structural diversity-oriented strategy based on the characteristic steric and stereoelectronic features of cyclopropane
基于环丙烷特征空间和立体电子特征的三维结构多样性导向策略的药物化学研究
  • 批准号:
    24390023
  • 财政年份:
    2012
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Investigation of the mechanism of insulin secretion via Ca
Ca 分泌胰岛素机制的研究
  • 批准号:
    23659049
  • 财政年份:
    2011
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Useful β-turn mimetics having three-dimensional diversity
具有三维多样性的有用的β-转角模拟物
  • 批准号:
    21390028
  • 财政年份:
    2009
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of ligands active specifically in intracellular Ca^<2+>-mobilizing second messenger system
开发在细胞内Ca^2-动员第二信使系统中具有特异性活性的配体
  • 批准号:
    17390027
  • 财政年份:
    2005
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of histamine H_3 receptor selective ligands based on the versatile chiral cyclopropane units.
基于多功能手性环丙烷单元开发组胺 H_3 受体选择性配体。
  • 批准号:
    15590096
  • 财政年份:
    2003
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of New Silicon Tethers and Their Application to the Synthesis of Anti-HIV Nucleosides
新型硅链的研制及其在抗HIV核苷合成中的应用
  • 批准号:
    13672203
  • 财政年份:
    2001
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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