(1R,3R,4R,5R,7S)-7-benzyloxy-1-benzyloxymethyl-5-benzyloxyamino-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane | 1186024-01-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1R,3R,4R,5R,7S)-7-benzyloxy-1-benzyloxymethyl-5-benzyloxyamino-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
• 英文别名: 5-methyl-1-[(1R,3R,4R,5R,7S)-7-phenylmethoxy-5-(phenylmethoxyamino)-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-3-yl]pyrimidine-2,4-dione
• CAS: 1186024-01-0
• 化学式: C₃₃H₃₅N₃O₆
• 分子量: 569.657
• InChiKey: JTDWONXVAPMTIP-GWRRIICGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  98.4
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,3R,4R,5R,7S)-7-benzyloxy-1-benzyloxymethyl-5-benzyloxyamino-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane 在 palladium 10% on activated carbon 、 甲酸铵 作用下， 以 甲醇 为溶剂， 反应 4.0h， 生成 1-[(1R,3R,4R,5R,7S)-5-amino-7-phenylmethoxy-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-3-yl]-5-methylpyrimidine-2,4-dione
  参考文献：
  名称：

  Synthesis of Conformationally Locked Carba-LNAs through Intramolecular Free-Radical Addition to C═N. Electrostatic and Steric Implication of the Carba-LNA Substituents in the Modified Oligos for Nuclease and Thermodynamic Stabilities

  摘要：

  The syntheses of the hitherto unavailable parentfully unsubstituted carba-LNA and its C7'-amino and/or C6'-hydroxyl substituted derivatives, have been accomplished by the intramolecular 5-exo free-radical addition to a C4'-tethered C=N to give carba-LNAs with variable hydrophilic substituents at C6'/C7' (amino and/or hydroxyl). They have been introduced into isosequential antisense oligonucleotides (AONs) to examine how their relative electrostatic and steric effects in the minor groove of a putative AON-RNA duplex affect the target affinity, nuclease resistance, and RNase H elicitation. We show that 2'-oxygen in LNA is important in stabilizing the DNA/DNA and DNA/RNA duplexes vis-a-vis the unsubstituted carba-LNA and its other derivatives and that hydrophobic groups at C6'/C7' in both carba-LNA and carba-ENA relatively destabilize the AON/DNA duplex more profoundly than those in the AON/RNA duplexes. Two main factors affect the relative stabilities of AON/DNA versus AON/RNA duplexes: (i) hydration in the minor groove depending upon hydrophilicity vis-a-vis hydrophobicity of the substituents, and (ii) the relative size of the minor groove in the AON/DNA versus AON/RNA duplexes dictates the steric clash with the substituents depending upon their relative chiralities. We also show how the chirality and chemical nature of the C6'/C7' substituents affect the nuclease stability as well as the thermal stability and the RNase recruitment by AON/RNA duplexes.

  DOI：

  10.1021/jo901009w
• 作为产物：
  描述：

  4'-(benzyloxyimino)ethyl-2'-hydroxy-3',5'-di-O-benzyl-thymidine 在 吡啶 、 偶氮二异丁腈 、 三正丁基氢锡 作用下， 反应 5.0h， 生成 (1R,3R,4R,5R,7S)-7-benzyloxy-1-benzyloxymethyl-5-benzyloxyamino-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
  参考文献：
  名称：

  远端二键与三键电负性氧取代基效应控制在构象锁定的戊呋喃糖（双环[2.2.1]庚烷）系统中将C-亚硝基官能团转化为相应的肟的动力学和热力学。

  摘要：

  我们报告了高产和可扩展非对映异构体合成的异构双环[2.2.1]庚烷-7-和-8-肟及其相应的C-亚硝基衍生物，它们是合成碳核苷的关键中间体。（C 7- R）-亚硝基-和（C 8 -S）-亚硝基双环庚烷体系都不需要DMSO- d 6中的任何外部碱来提供相应的肟，并且未观察到从肟到C-亚硝基化合物的反向异构化。的（C 8 -C转化小号）亚硝基化合物与È / Ž -oximes为〜8倍的速度（在40℃）比的（C7- ř）-亚硝基衍生物。该机制涉及用于（C7- R）-或（C8- S）-亚硝基衍生物转化为相应的E / Z-肟的一级反应动力学。与（C8- S）-亚硝基衍生物相比，（C7- R）-亚硝基化合物向相应肟的转化率较低，这是由于酸性H8电离中心距离OPMB两个键后者中C1上的C1 OMe基团与H1距离较远，而C7中的H7与C1 OMe基团相距三个键，使得后者中C1的吸电子基团的作用更强。

  DOI：

  10.1021/jo500266k

文献信息

• Synthesis of Conformationally Locked Carba-LNAs through Intramolecular Free-Radical Addition to C═N. Electrostatic and Steric Implication of the Carba-LNA Substituents in the Modified Oligos for Nuclease and Thermodynamic Stabilities
  作者：Jianfeng Xu、Yi Liu、Christelle Dupouy、Jyoti Chattopadhyaya

  DOI：10.1021/jo901009w

  日期：2009.9.4

  The syntheses of the hitherto unavailable parentfully unsubstituted carba-LNA and its C7'-amino and/or C6'-hydroxyl substituted derivatives, have been accomplished by the intramolecular 5-exo free-radical addition to a C4'-tethered C=N to give carba-LNAs with variable hydrophilic substituents at C6'/C7' (amino and/or hydroxyl). They have been introduced into isosequential antisense oligonucleotides (AONs) to examine how their relative electrostatic and steric effects in the minor groove of a putative AON-RNA duplex affect the target affinity, nuclease resistance, and RNase H elicitation. We show that 2'-oxygen in LNA is important in stabilizing the DNA/DNA and DNA/RNA duplexes vis-a-vis the unsubstituted carba-LNA and its other derivatives and that hydrophobic groups at C6'/C7' in both carba-LNA and carba-ENA relatively destabilize the AON/DNA duplex more profoundly than those in the AON/RNA duplexes. Two main factors affect the relative stabilities of AON/DNA versus AON/RNA duplexes: (i) hydration in the minor groove depending upon hydrophilicity vis-a-vis hydrophobicity of the substituents, and (ii) the relative size of the minor groove in the AON/DNA versus AON/RNA duplexes dictates the steric clash with the substituents depending upon their relative chiralities. We also show how the chirality and chemical nature of the C6'/C7' substituents affect the nuclease stability as well as the thermal stability and the RNase recruitment by AON/RNA duplexes.
• Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent Effect Controls the Kinetics and Thermodynamics of the Conversion of a <i>C</i>-Nitroso Function to the Corresponding Oxime in the Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane) System
  作者：Mansoureh Karimiahmadabadi、Sayeh Erfan、Andras Földesi、Jyoti Chattopadhyaya

  DOI：10.1021/jo500266k

  日期：2014.8.15

  We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo[2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d6 to afford the corresponding oxime, and no reverse isomerization

  我们报告了高产和可扩展非对映异构体合成的异构双环[2.2.1]庚烷-7-和-8-肟及其相应的C-亚硝基衍生物，它们是合成碳核苷的关键中间体。（C 7- R）-亚硝基-和（C 8 -S）-亚硝基双环庚烷体系都不需要DMSO- d 6中的任何外部碱来提供相应的肟，并且未观察到从肟到C-亚硝基化合物的反向异构化。的（C 8 -C转化小号）亚硝基化合物与È / Ž -oximes为〜8倍的速度（在40℃）比的（C7- ř）-亚硝基衍生物。该机制涉及用于（C7- R）-或（C8- S）-亚硝基衍生物转化为相应的E / Z-肟的一级反应动力学。与（C8- S）-亚硝基衍生物相比，（C7- R）-亚硝基化合物向相应肟的转化率较低，这是由于酸性H8电离中心距离OPMB两个键后者中C1上的C1 OMe基团与H1距离较远，而C7中的H7与C1 OMe基团相距三个键，使得后者中C1的吸电子基团的作用更强。