diethyl difluoro[(1R*,2R*)-2-(hydroxymethyl)cyclopropyl]methylphosphonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: diethyl difluoro[(1R*,2R*)-2-(hydroxymethyl)cyclopropyl]methylphosphonate
• 英文别名: trans-1-(diethoxyphosphinyl)difluoromethyl-2-hydroxymethylcyclopropane；[(1R,2R)-2-[[diethoxy(oxido)phosphaniumyl]-difluoromethyl]cyclopropyl]methanol
• 化学式: C₉H₁₇F₂O₄P
• 分子量: 258.202
• InChiKey: RSVVLNHQAURKLG-JGVFFNPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  16
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  61.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  diethyl difluoro[(1R*,2R*)-2-(hydroxymethyl)cyclopropyl]methylphosphonate 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 diethyl difluoro[(1S*,2S*)-2-formylcyclopropyl]methylphosphonate
  参考文献：
  名称：

  Stereoselective Reduction of Cyclopropylalkaones Possessing a Difluoromethylenephosphonate Group at the Ring: Application to Stereoselective Synthesis of Novel Cyclopropane Nucleotide Analogues

  摘要：

  Difluoro{(1S*,2S*)-2-[(1S*)-1-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl]cyclopropyl}methylphosphonic acid 12a and the related analogues were prepared as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1S*,2S*)-2-acethylcyclopropyl](difluoro)methylphosphonate 8a with K-Selectride at a low temperature proceeded from the less-hindered face of the carbonyl in the bisected s-cis conformation to give the corresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). In an analogous manner, several cyclopropylalkanols 8b-g possessing a difluoromethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide analogue 12a through a conventional method. The diastercomeric nucleotide analogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary results on an assay of PNP inhibitory activity of 9a and 15 are presented. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(00)00620-7
• 作为产物：
  描述：

  溴氟甲基膦酸二乙酯 在 锂硼氢 、 sodium hydride 、 锌 作用下， 以 乙醚 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 diethyl difluoro[(1R*,2R*)-2-(hydroxymethyl)cyclopropyl]methylphosphonate
  参考文献：
  名称：

  Convenient Synthesis of Cyclopropylalkanol Derivatives Possessing a Difluoromethylenephosphonate Group at the Ring

  摘要：

  DOI：

  10.1021/jo990922o

文献信息

• Synthesis of (2′S,3′S)-9-(4′-phosphono-4′,4′-difluoro-2′,3′-methanobutyl)guanine and its enantiomer. Evaluation of the inhibitory activity for purine nucleoside phosphorylase
  作者：Tsutomu Yokomatsu、Mutsumi Sato、Hiroshi Abe、Kenji Suemune、Keita Matsumoto、Taro Kihara、Shinji Soeda、Hiroshi Shimeno、Shiroshi Shibuya

  DOI：10.1016/s0040-4020(97)00704-7

  日期：1997.8

  Conformationally constrained analogues 2a and ent-2a of 9-(difluorophosphonopentyl)guanines 1, a multi-substrate analogue inhibitor of PNP, were prepared from optically active trans-1-(diethoxyphosphinyl)difluromethy-2-hydroxymethylcyclopropanes (+)-6 and (-)-6, Enzymatic double resolution was applied to obtain (+)-6 and (-)-6 with high enantiomeric purity. Inhibitory activity of 2a and ent-2a were found to be 2400-fold less potent than 1. (C) 1997 Elsevier Science Ltd.
• Synthesis of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids and the related methano analogues. Remarkable effect of the nucleobases and the cyclopropane rings on inhibitory activity toward purine nucleoside phosphorylase
  作者：Tsutomu Yokomatsu、Hiroshi Abe、Mutsumi Sato、Kenji Suemune、Taro Kihara、Shinji Soeda、Hiroshi Shimeno、Shiroshi Shibuya

  DOI：10.1016/s0968-0896(98)80023-0

  日期：1998.12

  A series of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids, (E)-2a,b and (Z)-2a,b, as well as the related methano analogues (+/-)-3a,b and (+/-)-4a,b were prepared for evaluation of their PNP inhibitory activities. The cyclopopane ring and the hypoxanthine residue were found to increase the profile of inhibitory activity. The IC50 and K-i values of difluoro(1R*,2S*)-2-[2-(6-oxo-6,9-dihydro-1H-9-purinyl)ethyl]cyclopropyl)methylphosphonic acid (+/-)3b toward PNP purified from Cellulomonas sp. were determined to be 70 nM and 8.8 nM, respectively. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Convenient Synthesis of Cyclopropylalkanol Derivatives Possessing a Difluoromethylenephosphonate Group at the Ring
  作者：Tsutomu Yokomatsu、Hiroshi Abe、Takehiro Yamagishi、Kenji Suemune、Shiroshi Shibuya

  DOI：10.1021/jo990922o

  日期：1999.10.1
• Stereoselective Reduction of Cyclopropylalkaones Possessing a Difluoromethylenephosphonate Group at the Ring: Application to Stereoselective Synthesis of Novel Cyclopropane Nucleotide Analogues
  作者：Tsutomu Yokomatsu、Takehiro Yamagishi、Kenji Suemune、Hiroshi Abe、Taro Kihara、Shinji Soeda、Hiroshi Shimeno、Shiroshi Shibuya

  DOI：10.1016/s0040-4020(00)00620-7

  日期：2000.9

  Difluoro(1S*,2S*)-2-[(1S*)-1-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl]cyclopropyl}methylphosphonic acid 12a and the related analogues were prepared as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1S*,2S*)-2-acethylcyclopropyl](difluoro)methylphosphonate 8a with K-Selectride at a low temperature proceeded from the less-hindered face of the carbonyl in the bisected s-cis conformation to give the corresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). In an analogous manner, several cyclopropylalkanols 8b-g possessing a difluoromethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide analogue 12a through a conventional method. The diastercomeric nucleotide analogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary results on an assay of PNP inhibitory activity of 9a and 15 are presented. (C) 2000 Elsevier Science Ltd. All rights reserved.