(1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-hydroxy-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane | 1186024-07-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-hydroxy-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
• 英文别名: 1-[(1R,3R,4R,5S,7S)-5-hydroxy-7-phenylmethoxy-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-3-yl]-5-methylpyrimidine-2,4-dione
• CAS: 1186024-07-6
• 化学式: C₂₆H₂₈N₂O₆
• 分子量: 464.518
• InChiKey: ZOIAKQWYZWMGHI-BYVFKEDWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  97.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  二硫化碳 、 (1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-hydroxy-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane 、 碘甲烷 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 以65%的产率得到(1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-((methylthio)thiocarbonyl)oxy-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
  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：

  5-methyl-1-[(1R,3R,4R,7S)-5-oxo-7-phenylmethoxy-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-3-yl]pyrimidine-2,4-dione 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以226 mg的产率得到(1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-hydroxy-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
  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