(1R,3R,4R,5S,6S,7S)-7-(benzyloxy)-1-((benzyloxy)methyl)-5-methyl-6-tosylate-3-(thymin-1-yl)-2-oxabicyclo[2.2.1]heptane | 1147324-87-5

• 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,5S,6S,7S)-7-(benzyloxy)-1-((benzyloxy)methyl)-5-methyl-6-tosylate-3-(thymin-1-yl)-2-oxabicyclo[2.2.1]heptane
• 英文别名: [(1R,3R,4R,5S,6S,7S)-5-methyl-3-(5-methyl-2,4-dioxopyrimidin-1-yl)-7-phenylmethoxy-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-6-yl] 4-methylbenzenesulfonate
• CAS: 1147324-87-5
• 化学式: C₃₄H₃₆N₂O₈S
• 分子量: 632.734
• InChiKey: UVNBENHQWCKFSR-JDIUSSNSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  45
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  129
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1R,3R,4R,5S,6S,7S)-7-(benzyloxy)-1-((benzyloxy)methyl)-5-methyl-6-tosylate-3-(thymin-1-yl)-2-oxabicyclo[2.2.1]heptane 在 palladium hydroxide on carbon 、 甲酸铵 作用下， 以 甲醇 为溶剂， 反应 5.0h， 生成 [(1R,3R,4R,5S,6S,7S)-7-hydroxy-1-(hydroxymethyl)-5-methyl-3-(5-methyl-2,4-dioxopyrimidin-1-yl)-2-oxabicyclo[2.2.1]heptan-6-yl] 4-methylbenzenesulfonate
  参考文献：
  名称：

  Double Sugar and Phosphate Backbone-Constrained Nucleotides: Synthesis, Structure, Stability, and Their Incorporation into Oligodeoxynucleotides

  摘要：

  Two diastereomerically pure carba-LNA dioxaphosphorinane nucleotides [(S-p)- or (R-p)-D-2-CNA], simultaneously conformationally locked at the sugar and the phosphate backbone, have been designed and synthesized. Structural studies by NMR as well as by ab initio calculations showed that in (S-p)- and (R-p)-D-2-CNA the Mowing occur: (i) the sugar is locked in extreme North-type conformation with P = 11 degrees and Phi(m) (ii) the six-membered 1,3,2-dioxaphosphorinane ring adopts a half-chair conformation; (iii) the fixed phosphate backbone delta, epsilon, and zeta torsions were found to be delta [gauch(+)], epsilon (cis), zeta[anticlinal(+)] for (S-p)-D-2-CNA, and delta [gaitche(+)], epsilon(cis), zeta[anticlittal(-)] for (R-p)-D-2-CNA. It has been found that F- ion can catalyze the isomerization of pure (S-p)-D-2-CNA or (R-p)-D-2-CNA to give an equilibrium mixture (K = 1.94). It turned out that at equilibrium concentration the (S-p)-D-2-CNA isomer is preferred over the (R-p)-D-2-CNA isomer by 0.39 kcal/mol. The chemical reactivity of the six-membered dioxaphosphorinane ring in D-2-CNA was found to be dependent on the internucleotidic phosphate stereochemistry. Thus, both (Sp)- and (Rp)-D2-CNA dimers (17a and 17b) were very labile toward nucleophile attack in concentrated aqueous ammonia [t(1/2) = 12 and 6 min, respectively] to give carba-LNA-6',5'-phosphodiester (21) approximate to 70-90%, carba-LNA-3',5'-phosphodiester (22) approximate to 10%, and carba-LNA-6',3'-phosphodiester (23) < 10%. In contrasts the (S-p)-D-2-CNA was about 2 times more stable than (Rp)-D2-CNA under hydrazine hydrate/pyficfine/AcOH (pH = 5.6) [t(1/2) = 178 and 99 h, respectively], which was exploited in the deprotection of pure (S-p)-D-2-CNA incorporated antisense oligodeoxynucleotides (AON). Thus, after removal of the solid supports from the (S-p)-D-2-CNA-modified AON by BDU/MeCN, they were treated with hydrazine hydrate in pyridine/AcOH to give pure AONs in 35-40% yield, which was unequivocally characterized by MALDI-TOF to show that they have an intact six-membered dioxaphosphorinane ring. The effect of pure (S-p)-D-2-CNA niodification in the AONs was estimated by complexing to the complementary RNA and DNA strands by the thermal denaturation studies. This showed that this cyclic phosphotriester modification destabilizes the AON/DNA and AON/RNA duplex by about -6 to -9 degrees C/modification. Treatment of (Sp)-D-2-CNA-modified AON with concentrated aqueous ammonia gave cwba-LNA-6',5'-phosphodiester modified AON (similar to 80%) plus a small amount of carba-LNA-3',5'-Phosphodiester-modified AON (similar to 20%). It is noteworthy that Carba-LNA-3',5'-phosphodiester modification stabilized the AON/RNA duplex by +4 degrees C/modificafion (J. Org. Chem. 2009, 74, 118), whereas carba-LNA-6', 5'-phosphodiester modification destabilizes both AON/RNA and AON/DNA significantly (by -10 to -19 degrees C/modification), which, as shown in our comparative CD studies, that the cyclic phosphotriester modified AONs as well as carba-LNA-6'.5'-phosphodiester modified AONs are much more weakly stacked than carba-LNA-3',5'-phosphodiester-modified AONs.

  DOI：

  10.1021/jo900391n
• 作为产物：
  描述：

  (1R,3R,4R,5S,6S,7S)-7-benzyloxy-1-benzyloxymethyl-6-hydroxy-5-methyl-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane 、 对甲苯磺酰氯 在 吡啶 作用下， 反应 36.0h， 以94%的产率得到(1R,3R,4R,5S,6S,7S)-7-(benzyloxy)-1-((benzyloxy)methyl)-5-methyl-6-tosylate-3-(thymin-1-yl)-2-oxabicyclo[2.2.1]heptane
  参考文献：
  名称：

  Double Sugar and Phosphate Backbone-Constrained Nucleotides: Synthesis, Structure, Stability, and Their Incorporation into Oligodeoxynucleotides

  摘要：

  Two diastereomerically pure carba-LNA dioxaphosphorinane nucleotides [(S-p)- or (R-p)-D-2-CNA], simultaneously conformationally locked at the sugar and the phosphate backbone, have been designed and synthesized. Structural studies by NMR as well as by ab initio calculations showed that in (S-p)- and (R-p)-D-2-CNA the Mowing occur: (i) the sugar is locked in extreme North-type conformation with P = 11 degrees and Phi(m) (ii) the six-membered 1,3,2-dioxaphosphorinane ring adopts a half-chair conformation; (iii) the fixed phosphate backbone delta, epsilon, and zeta torsions were found to be delta [gauch(+)], epsilon (cis), zeta[anticlinal(+)] for (S-p)-D-2-CNA, and delta [gaitche(+)], epsilon(cis), zeta[anticlittal(-)] for (R-p)-D-2-CNA. It has been found that F- ion can catalyze the isomerization of pure (S-p)-D-2-CNA or (R-p)-D-2-CNA to give an equilibrium mixture (K = 1.94). It turned out that at equilibrium concentration the (S-p)-D-2-CNA isomer is preferred over the (R-p)-D-2-CNA isomer by 0.39 kcal/mol. The chemical reactivity of the six-membered dioxaphosphorinane ring in D-2-CNA was found to be dependent on the internucleotidic phosphate stereochemistry. Thus, both (Sp)- and (Rp)-D2-CNA dimers (17a and 17b) were very labile toward nucleophile attack in concentrated aqueous ammonia [t(1/2) = 12 and 6 min, respectively] to give carba-LNA-6',5'-phosphodiester (21) approximate to 70-90%, carba-LNA-3',5'-phosphodiester (22) approximate to 10%, and carba-LNA-6',3'-phosphodiester (23) < 10%. In contrasts the (S-p)-D-2-CNA was about 2 times more stable than (Rp)-D2-CNA under hydrazine hydrate/pyficfine/AcOH (pH = 5.6) [t(1/2) = 178 and 99 h, respectively], which was exploited in the deprotection of pure (S-p)-D-2-CNA incorporated antisense oligodeoxynucleotides (AON). Thus, after removal of the solid supports from the (S-p)-D-2-CNA-modified AON by BDU/MeCN, they were treated with hydrazine hydrate in pyridine/AcOH to give pure AONs in 35-40% yield, which was unequivocally characterized by MALDI-TOF to show that they have an intact six-membered dioxaphosphorinane ring. The effect of pure (S-p)-D-2-CNA niodification in the AONs was estimated by complexing to the complementary RNA and DNA strands by the thermal denaturation studies. This showed that this cyclic phosphotriester modification destabilizes the AON/DNA and AON/RNA duplex by about -6 to -9 degrees C/modification. Treatment of (Sp)-D-2-CNA-modified AON with concentrated aqueous ammonia gave cwba-LNA-6',5'-phosphodiester modified AON (similar to 80%) plus a small amount of carba-LNA-3',5'-Phosphodiester-modified AON (similar to 20%). It is noteworthy that Carba-LNA-3',5'-phosphodiester modification stabilized the AON/RNA duplex by +4 degrees C/modificafion (J. Org. Chem. 2009, 74, 118), whereas carba-LNA-6', 5'-phosphodiester modification destabilizes both AON/RNA and AON/DNA significantly (by -10 to -19 degrees C/modification), which, as shown in our comparative CD studies, that the cyclic phosphotriester modified AONs as well as carba-LNA-6'.5'-phosphodiester modified AONs are much more weakly stacked than carba-LNA-3',5'-phosphodiester-modified AONs.

  DOI：

  10.1021/jo900391n

文献信息

• Double Sugar and Phosphate Backbone-Constrained Nucleotides: Synthesis, Structure, Stability, and Their Incorporation into Oligodeoxynucleotides
  作者：Chuanzheng Zhou、Oleksandr Plashkevych、Jyoti Chattopadhyaya

  DOI：10.1021/jo900391n

  日期：2009.5.1

  Two diastereomerically pure carba-LNA dioxaphosphorinane nucleotides [(S-p)- or (R-p)-D-2-CNA], simultaneously conformationally locked at the sugar and the phosphate backbone, have been designed and synthesized. Structural studies by NMR as well as by ab initio calculations showed that in (S-p)- and (R-p)-D-2-CNA the Mowing occur: (i) the sugar is locked in extreme North-type conformation with P = 11 degrees and Phi(m) (ii) the six-membered 1,3,2-dioxaphosphorinane ring adopts a half-chair conformation; (iii) the fixed phosphate backbone delta, epsilon, and zeta torsions were found to be delta [gauch(+)], epsilon (cis), zeta[anticlinal(+)] for (S-p)-D-2-CNA, and delta [gaitche(+)], epsilon(cis), zeta[anticlittal(-)] for (R-p)-D-2-CNA. It has been found that F- ion can catalyze the isomerization of pure (S-p)-D-2-CNA or (R-p)-D-2-CNA to give an equilibrium mixture (K = 1.94). It turned out that at equilibrium concentration the (S-p)-D-2-CNA isomer is preferred over the (R-p)-D-2-CNA isomer by 0.39 kcal/mol. The chemical reactivity of the six-membered dioxaphosphorinane ring in D-2-CNA was found to be dependent on the internucleotidic phosphate stereochemistry. Thus, both (Sp)- and (Rp)-D2-CNA dimers (17a and 17b) were very labile toward nucleophile attack in concentrated aqueous ammonia [t(1/2) = 12 and 6 min, respectively] to give carba-LNA-6',5'-phosphodiester (21) approximate to 70-90%, carba-LNA-3',5'-phosphodiester (22) approximate to 10%, and carba-LNA-6',3'-phosphodiester (23) < 10%. In contrasts the (S-p)-D-2-CNA was about 2 times more stable than (Rp)-D2-CNA under hydrazine hydrate/pyficfine/AcOH (pH = 5.6) [t(1/2) = 178 and 99 h, respectively], which was exploited in the deprotection of pure (S-p)-D-2-CNA incorporated antisense oligodeoxynucleotides (AON). Thus, after removal of the solid supports from the (S-p)-D-2-CNA-modified AON by BDU/MeCN, they were treated with hydrazine hydrate in pyridine/AcOH to give pure AONs in 35-40% yield, which was unequivocally characterized by MALDI-TOF to show that they have an intact six-membered dioxaphosphorinane ring. The effect of pure (S-p)-D-2-CNA niodification in the AONs was estimated by complexing to the complementary RNA and DNA strands by the thermal denaturation studies. This showed that this cyclic phosphotriester modification destabilizes the AON/DNA and AON/RNA duplex by about -6 to -9 degrees C/modification. Treatment of (Sp)-D-2-CNA-modified AON with concentrated aqueous ammonia gave cwba-LNA-6',5'-phosphodiester modified AON (similar to 80%) plus a small amount of carba-LNA-3',5'-Phosphodiester-modified AON (similar to 20%). It is noteworthy that Carba-LNA-3',5'-phosphodiester modification stabilized the AON/RNA duplex by +4 degrees C/modificafion (J. Org. Chem. 2009, 74, 118), whereas carba-LNA-6', 5'-phosphodiester modification destabilizes both AON/RNA and AON/DNA significantly (by -10 to -19 degrees C/modification), which, as shown in our comparative CD studies, that the cyclic phosphotriester modified AONs as well as carba-LNA-6'.5'-phosphodiester modified AONs are much more weakly stacked than carba-LNA-3',5'-phosphodiester-modified AONs.