(1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-7-hydroxy-1-hydroxymethyl-6-methyl-2,5-dioxabicyclo[2.2.1]heptane | 1197033-12-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: (1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-7-hydroxy-1-hydroxymethyl-6-methyl-2,5-dioxabicyclo[2.2.1]heptane
• 英文别名: 9-[2,5-Anhydro-6-deoxy-4-(hydroxymethyl)-alpha-L-mannofuranosyl]-N-benzoyl-9H-purin-6-amine；N-[9-[(1R,3R,4R,6S,7S)-7-hydroxy-1-(hydroxymethyl)-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl]purin-6-yl]benzamide
• CAS: 1197033-12-7
• 化学式: C₁₉H₁₉N₅O₅
• 分子量: 397.39
• InChiKey: LDDFACWXKZYSFU-DZSXKSNSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  132
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-7-hydroxy-1-hydroxymethyl-6-methyl-2,5-dioxabicyclo[2.2.1]heptane 、 4,4'-双甲氧基三苯甲基氯 在 吡啶 作用下， 反应 16.0h， 以91%的产率得到(1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-1-(4,4'-dimethoxytrityloxymethyl)-7-hydroxy-6-methyl-2,5-dioxabicyclo[2.2.1]heptane
  参考文献：
  名称：

  Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′O-Methoxyethyl and 2′,4′-Constrained 2′O-Ethyl Nucleic Acid Analogues

  摘要：

  We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nuclecic acid (LNA) nucleosides yielded a series of nucleoside modification (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modification. The synthesis of the cMOE and eEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving group with clean inversion of stereochemistry was achieved under suprisingly mild conditions. For the S-cEt modification, the synthesis of all four (thymine, 5-methylcytosine, adenine, and guanine) nucleobase-modified phosphoramidites was accomplished on a multigram scale. Biophysical evaluation of the cMOE- and cEt-containing oligonucletides revealed that they possess hybridization and mismatch discrimination attributes similar to those of LNA but greatly improved resistance to exonuclease digestion.

  DOI：

  10.1021/jo902560f
• 作为产物：
  描述：

  (1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-1-(tert-butyldiphenylsilyloxymethyl)-7-hydroxy-6-methyl-2,5-dioxabicyclo[2.2.1]heptane 在 triethylamine tris(hydrogen fluoride) 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以94%的产率得到(1R,3R,4R,6S,7S)-3-(6-N-benzoyladenin-9-yl)-7-hydroxy-1-hydroxymethyl-6-methyl-2,5-dioxabicyclo[2.2.1]heptane
  参考文献：
  名称：

  Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′O-Methoxyethyl and 2′,4′-Constrained 2′O-Ethyl Nucleic Acid Analogues

  摘要：

  We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nuclecic acid (LNA) nucleosides yielded a series of nucleoside modification (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modification. The synthesis of the cMOE and eEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving group with clean inversion of stereochemistry was achieved under suprisingly mild conditions. For the S-cEt modification, the synthesis of all four (thymine, 5-methylcytosine, adenine, and guanine) nucleobase-modified phosphoramidites was accomplished on a multigram scale. Biophysical evaluation of the cMOE- and cEt-containing oligonucletides revealed that they possess hybridization and mismatch discrimination attributes similar to those of LNA but greatly improved resistance to exonuclease digestion.

  DOI：

  10.1021/jo902560f

文献信息

• Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′<i>O</i>-Methoxyethyl and 2′,4′-Constrained 2′<i>O</i>-Ethyl Nucleic Acid Analogues
  作者：Punit P. Seth、Guillermo Vasquez、Charles A. Allerson、Andres Berdeja、Hans Gaus、Garth A. Kinberger、Thazha P. Prakash、Michael T. Migawa、Balkrishen Bhat、Eric E. Swayze

  DOI：10.1021/jo902560f

  日期：2010.3.5

  We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nuclecic acid (LNA) nucleosides yielded a series of nucleoside modification (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modification. The synthesis of the cMOE and eEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving group with clean inversion of stereochemistry was achieved under suprisingly mild conditions. For the S-cEt modification, the synthesis of all four (thymine, 5-methylcytosine, adenine, and guanine) nucleobase-modified phosphoramidites was accomplished on a multigram scale. Biophysical evaluation of the cMOE- and cEt-containing oligonucletides revealed that they possess hybridization and mismatch discrimination attributes similar to those of LNA but greatly improved resistance to exonuclease digestion.