(1R,3R,4R,6S,7S)-1-(4,4'-dimethoxytrityloxymethyl)-7-hydroxy-6-methyl-3-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane | 1197033-21-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (1R,3R,4R,6S,7S)-1-(4,4'-dimethoxytrityloxymethyl)-7-hydroxy-6-methyl-3-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane
• 英文别名: 1-(2,5-Anhydro-4-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-6-deoxy-alpha-L-mannofuranosyl)-5-methylpyrimidine-2,4(1H,3H)-dione；1-[(1R,3R,4R,6S,7S)-1-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-7-hydroxy-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-5-methylpyrimidine-2,4-dione
• CAS: 1197033-21-8
• 化学式: C₃₃H₃₄N₂O₈
• 分子量: 586.642
• InChiKey: XCYNXNBWEYZWQQ-JTNNVKOGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1R,3R,4R,6S,7S)-1-(4,4'-dimethoxytrityloxymethyl)-7-hydroxy-6-methyl-3-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane 、 双(二异丙基氨基)(2-氰基乙氧基)膦 在 N-甲基咪唑 、 四氮唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 以98%的产率得到(1S,3R,4R,6S,7S)-7-[2-cyanoethoxy(diisopropylamino)phosphinoxy]-1-(4,4'-dimethoxytrityloxymethyl)-6-methyl-3-(thymin-1-yl)-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)-7-hydroxy-1-hydroxymethyl-6-methyl-3-(thymin-1-yl)-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70%的产率得到(1R,3R,4R,6S,7S)-1-(4,4'-dimethoxytrityloxymethyl)-7-hydroxy-6-methyl-3-(thymin-1-yl)-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

• [EN] LINKAGE MODIFIED OLIGOMERIC COMPOUNDS<br/>[FR] COMPOSÉS OLIGOMÈRES MODIFIÉS PAR LIAISON
  申请人：ISIS PHARMACEUTICALS INC

  公开号：WO2015168172A1

  公开（公告）日：2015-11-05

  The present invention provides oligomeric compounds comprising at least one neutral methoxypropyl phosphonate modified internucleoside linkage. Such oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Such oligomeric compounds have enhanced stability to exposure to base during synthesis. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

  本发明提供了含有至少一种中性甲氧基丙基磷酸酯修饰的核苷间连接的寡聚化合物。这种寡聚化合物具有一个或多个改进的性质，如选择性、效力、改进的毒性谱和/或改进的促炎谱。这种寡聚化合物在合成过程中对碱的暴露具有增强的稳定性。某些这种寡聚化合物对于与细胞中的互补核酸杂交是有用的，包括但不限于核酸。在某些实施例中，杂交导致调节细胞中目标核酸的活性或表达量。
• 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.