1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)nicotinamide-5'-phosphate | 133473-75-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 吡啶核苷酸
• 英文名称: 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)nicotinamide-5'-phosphate
• 英文别名: β-2'-deoxy-2'-fluoroarabinonicotinamide mononucleotide；arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide；[(2R,3R,4S,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-4-fluoro-3-hydroxyoxolan-2-yl]methyl hydrogen phosphate
• CAS: 133473-75-3
• 化学式: C₁₁H₁₄FN₂O₇P
• 分子量: 336.214
• InChiKey: ZSLVMKOWTYOSOT-PKIKSRDPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  146
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)nicotinamide-5'-phosphate 、 5’-三磷酸腺苷 在 pyrophosphatase 、 magnesium chloride 作用下， 以 水 为溶剂， 反应 1.0h， 以95%的产率得到2'-deoxy-2'-fluoroarabino-NAD+
  参考文献：
  名称：

  Diastereocontrolled Electrophilic Fluorinations of 2-Deoxyribonolactone: Syntheses of All Corresponding 2-Deoxy-2-fluorolactones and 2′-Deoxy-2′-fluoro-NAD⁺s

  摘要：

  Methods to construct 2'-deoxy-2'-fluoro nucleosides have undergone limited improvement in the last 20 years in spite of the substantially increased value of these compounds as pharmaceuticals and as tools for studying biological processes. We herein describe a consolidated approach to synthesize precursors to these commercially and scientifically valuable compounds via diastereocontrolled fluorination of the readily available precursor 2-deoxy-D-ribonolactone. With employment of appropriate sterically bulky silyl protecting groups at the 3 and 5 positions, controlled electrophilic fluorination of the Li-ribonolactone enolate by N-fluorodibenzenesulfonamide yielded the corresponding 2-deoxy-2-fluoroarabinolactone in high isolated yield (72%) The protected 2-deoxy-2,2-difluororibonolactone was obtained similarly in high yield from a second round of electrophilic fluorination (two steps, 51% from protected ribonolactone starting material). Accomplishment of the difficult ribofluorination of the lactone was achieved by the directive effects of a diastereoselectively installed (x-trimethylsilyl group. Electrophilic fluorination of a protected 2-deoxy-2-trimethylsilylarabinolactone via enolate generation provided the protected 2-deoxy-2-fluororibolactone as the exclusive fluorinated product. The reaction also yielded the starting material, the desilylated protected 2-deoxyribonolactone, which was recycled to provide a 38% chemical yield of the fluorinated product (versus initial protected ribonolactone),after consecutive silylation and fluorination cycles. Using our fluorinated sugar precursors, we prepared the 2'-fluoroarabino-, 2'-fluororibo-, and 2',2'-difluoronicotinamide adenine dinucleotides (NAD(+)) of potential biological interest. These syntheses provide the most consolidated and efficient methods for production of sugar precursors of 2'-deoxy-2'-fluoronucleosides and have the advantage of utilizing an air-stable electrophilic fluorinating agent. The fluorinated NAD(+)s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes.

  DOI：

  10.1021/jo900637f
• 作为产物：
  描述：

  2-fluoro-2-deoxy-3-O-acetyl-5-O-(p-nitrobenzoyl)-D-arabinofuranosyl bromide 在 焦磷酰氯 、 氨 作用下， 以 various solvent(s) 为溶剂， 反应 22.0h， 生成 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)nicotinamide-5'-phosphate
  参考文献：
  名称：

  Pyridine coenzyme analogs. 3. Synthesis of three NAD+ analogs containing a 2'-deoxy-2'-substituted nicotinamide arabinofuranosyl moiety

  摘要：

  A general method for the preparation of 2'-deoxy-2'-substituted arabino-nicotinamide-adenine dinucleotide (NAD) analogues is described. Starting from 1,2:5,6-di-O-isopropylidine-alpha-D-allofuranose, the 2'-amino-, 2'-azido-, and 2'-fluoro-arabino-NAD analogues have been prepared. We report an improved phosphorylation procedure for nicotinamide nucleosides using pyrophosphoryl chloride in m-cresol. The selective reduction of azido substituents by aqueous dithiothreitol (DTT) in the presence of the readily reducible nicotinamide moiety is also reported. With both the 2'-azido and the 2'-fluoro substituents the cis configuration predominates for the incoming nicotinamide, thus allowing the stereoselective formation of the beta anomer in high yield.

  DOI：

  10.1021/jo00011a029

文献信息

• Studies on the Synthesis of Nicotinamide Nucleoside and Nucleotide Analogues and Their Inhibitions towards CD38 NADase
  作者：Liangren Zhang、Anna Ka Yee Kwong、Zhenjun Yang、Zhe Chen、Hon Cheung Lee、Lihe Zhang

  DOI：10.3987/com-11-12361

  日期：——

  Nicotinamide adenine dinucleotide (NAD) analogues inhibit the NADase activity of CD38. In the current study, efficient protocols for the synthesis of substituted-nicotinamide nucleosides and nucleotides were developed. The one-pot phosphorylation esterification strategy provides a convenient way of obtaining nicotinamide nucleoside phosphodiesters from the corresponding nucleosides. Structure activity relationship information revealed that replacement of 3'-hydroxy group with F or N-3 led to the considerably decrease of activity as compared with ara-F NMN. Phosphodiesterification of nicotinamide nucleosides lowers their inhibitory activities in some extent.
• Pyridine coenzyme analogs. 3. Synthesis of three NAD+ analogs containing a 2'-deoxy-2'-substituted nicotinamide arabinofuranosyl moiety
  作者：Paul R. Sleath、Anthony L. Handlon、Norman J. Oppenheimer

  DOI：10.1021/jo00011a029

  日期：1991.5

  A general method for the preparation of 2'-deoxy-2'-substituted arabino-nicotinamide-adenine dinucleotide (NAD) analogues is described. Starting from 1,2:5,6-di-O-isopropylidine-alpha-D-allofuranose, the 2'-amino-, 2'-azido-, and 2'-fluoro-arabino-NAD analogues have been prepared. We report an improved phosphorylation procedure for nicotinamide nucleosides using pyrophosphoryl chloride in m-cresol. The selective reduction of azido substituents by aqueous dithiothreitol (DTT) in the presence of the readily reducible nicotinamide moiety is also reported. With both the 2'-azido and the 2'-fluoro substituents the cis configuration predominates for the incoming nicotinamide, thus allowing the stereoselective formation of the beta anomer in high yield.
• Diastereocontrolled Electrophilic Fluorinations of 2-Deoxyribonolactone: Syntheses of All Corresponding 2-Deoxy-2-fluorolactones and 2′-Deoxy-2′-fluoro-NAD⁺s
  作者：Yana Cen、Anthony A. Sauve

  DOI：10.1021/jo900637f

  日期：2009.8.21

  Methods to construct 2'-deoxy-2'-fluoro nucleosides have undergone limited improvement in the last 20 years in spite of the substantially increased value of these compounds as pharmaceuticals and as tools for studying biological processes. We herein describe a consolidated approach to synthesize precursors to these commercially and scientifically valuable compounds via diastereocontrolled fluorination of the readily available precursor 2-deoxy-D-ribonolactone. With employment of appropriate sterically bulky silyl protecting groups at the 3 and 5 positions, controlled electrophilic fluorination of the Li-ribonolactone enolate by N-fluorodibenzenesulfonamide yielded the corresponding 2-deoxy-2-fluoroarabinolactone in high isolated yield (72%) The protected 2-deoxy-2,2-difluororibonolactone was obtained similarly in high yield from a second round of electrophilic fluorination (two steps, 51% from protected ribonolactone starting material). Accomplishment of the difficult ribofluorination of the lactone was achieved by the directive effects of a diastereoselectively installed (x-trimethylsilyl group. Electrophilic fluorination of a protected 2-deoxy-2-trimethylsilylarabinolactone via enolate generation provided the protected 2-deoxy-2-fluororibolactone as the exclusive fluorinated product. The reaction also yielded the starting material, the desilylated protected 2-deoxyribonolactone, which was recycled to provide a 38% chemical yield of the fluorinated product (versus initial protected ribonolactone),after consecutive silylation and fluorination cycles. Using our fluorinated sugar precursors, we prepared the 2'-fluoroarabino-, 2'-fluororibo-, and 2',2'-difluoronicotinamide adenine dinucleotides (NAD(+)) of potential biological interest. These syntheses provide the most consolidated and efficient methods for production of sugar precursors of 2'-deoxy-2'-fluoronucleosides and have the advantage of utilizing an air-stable electrophilic fluorinating agent. The fluorinated NAD(+)s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes.