diethyl <1,1-difluoro-3(S),4-dihydroxybutyl>phosphonate | 157318-62-2

• 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 <1,1-difluoro-3(S),4-dihydroxybutyl>phosphonate
• 英文别名: diethyl 1,1-difluoro-(3S)-3,4-dihydroxybutylphosphonate；diethyl [1,1-difluoro-3-(3S),4-dihydroxybutyl]phosphonate；diethyl [1,1-difluoro-3(S),4-dihydroxybutyl]phosphonate；(2S)-4-diethoxyphosphoryl-4,4-difluorobutane-1,2-diol
• CAS: 157318-62-2
• 化学式: C₈H₁₇F₂O₅P
• 分子量: 262.191
• InChiKey: GIMOFADTCDVETM-ZETCQYMHSA-N

物化性质

• 沸点：
  372.8±42.0 °C(Predicted)
• 密度：
  1.286±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  16
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  diethyl <1,1-difluoro-3(S),4-dihydroxybutyl>phosphonate 在 三甲基溴硅烷 、 水 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 反应 5.5h， 以75%的产率得到1,1-difluoro-3(S),4-dihydroxybutylphosphonic acid
  参考文献：
  名称：

  环状磷脂酸的硫代磷酸酯和氟代亚甲基膦酸酯类似物：溶血磷脂酸受体的新型拮抗剂。

  摘要：

  溶血磷脂酸（LPA）G蛋白偶联受体（GPCR）的同工型选择性拮抗剂在细胞生物学和临床应用中具有重要的潜在用途。通过化学合成制备了新的碳环磷脂酸（ccPA）的硫代磷酸酯和氟代亚甲基膦酸酯类似物。使用Yasuda-Shedlovsky外推法滴定法测量了这些两亲性磷脂和母体环状膦酸酯的pKa值。在表达单个EDG家族GPCR的RH7777细胞中，使用Ca2 +动员测定法，针对LPA受体（LPAR）亚型特异性激动剂和拮抗剂活性，对这些和其他ccPA类似物的药理特性进行了表征。特别是，硫代磷酸膦酸酯ccPA类似物通过LPA1 / LPA3激活抑制Ca2 +释放，并且是LPA1 / LPA3拮抗剂。单氟亚甲基膦酸酯ccPA类似物也是有效的LPA1 / LPA3拮抗剂。相反，二氟亚甲基膦酸酯ccPA类似物是弱LPAR激动剂，而ccPA本身既没有激动剂也没有拮抗剂活性。

  DOI：

  10.1021/jm060351+
• 作为产物：
  描述：

  diethyl (2R,3S) or (2S,3S)-3,4-dihydroxy-1,1-difluoro-2-hydroxy-3,4-O-isopropylidenebutylphosphonate 在 三正丁基氢锡 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 甲苯 为溶剂， 反应 2.75h， 生成 diethyl <1,1-difluoro-3(S),4-dihydroxybutyl>phosphonate
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Phospholipid Analogs as Inhibitors of the Bacterial Phospholipase C from Bacillus cereus

  摘要：

  Enzymes belonging to the phospholipase C (PLC) family hydrolyze the phosphodiester bond of phospholipids to give a diacylglycerol and a phosphorylated head group. The bacterial phospholipase C from Bacillus cereus (PLC(Bc)) has been studied extensively, and there is a wealth of information regarding those structural features that are important for substrate activity. In contrast, there is virtually no data available regarding structure-activity relationships for inhibitors of this enzyme. To address this shortcoming, a series of optically pure analogues of 1,2-dihexanoyl-sn-glycero-3-phosphocholine (2) containing different replacements of the phosphate group were first synthesized including the phosphoramidates 4 and 8, the phosphonate 5, the (difluoromethylene)phosphonate 6, the thiophosphate 7, the diastereomeric phosphorothioates 9 and 10, and the phosphorodithioate 11. Each of these phosphatidylcholine derivatives was tested for inhibitor or substrate activity with PLC(Bc) using the water-soluble phosphatidylcholine 2 as the monomeric substrate. The measurements were conducted below the critical micellar concentrations of both 2 and the inhibitor. Of the analogues, only 7 and 9 underwent observable enzymatic hydrolysis under the assay conditions used. The k(cat) of the (Sp)-phosphorothioate 9 was approximately one-fifth that of 2, and when compared to 2, 7 was hydrolyzed only very slowly by the enzyme. Kinetic studies indicated that the phospholipid analogues tested were competitive inhibitors with increasing K-i's follows: 7 approximate to 11 approximate to 10 < 4 approximate to 8 < 5 approximate to 6.

  DOI：

  10.1021/jo00096a024

文献信息

• Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid
  作者：Yong Xu、Yimin Fang、Jie Chen、Glenn D. Prestwich

  DOI：10.1016/j.bmcl.2004.01.020

  日期：2004.3

  Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an alpha-monofluoromethylene (-CHF-) or alpha-difluoromethylene (-CF(2)-) moiety using hydrolytic kinetic resolution (HKR) of a racemic epoxide as the key step. Since PA activates signaling in the mTOR (mammalian target of rapamycin) pathway, these metabolically stabilized PA analogues were evaluated

  合成了磷脂酸（PA）的膦酸酯类似物，其中使用消旋体的水解动力学拆分（HKR）将桥联氧替换为α-单氟亚甲基（-CHF-）或α-二氟亚甲基（-CF（2）-）部分环氧是关键步骤。由于PA激活了mTOR（雷帕霉素的哺乳动物靶标）途径中的信号传导，因此在静止的HEK 293细胞中评估了这些代谢稳定的PA类似物。这些类似物中的大多数在激活S6激酶（mTOR信号的下游靶标）方面超过了PA。对于单-和二氟亚甲基膦酸酯，非天然（2R）类似物的活性均比天然（2S）对映异构体小。
• Synthesis of Chiral (α,α-Difluoroalkyl)phosphonate Analogues of (Lyso)phosphatidic Acid via Hydrolytic Kinetic Resolution
  作者：Yong Xu、Glenn D. Prestwich

  DOI：10.1021/ol026684s

  日期：2002.11.1

  alpha-difluoroalkyl)phosphonates were obtained after selective esterification and deprotection of the corresponding phosphonates. These compounds are novel phosphatase-resistant analogues of lysophosphatidic acid and phosphatidic acid. [reaction: see text]

  使用手性salen-Co络合物水解1,1-二氟-3,4-环氧丁基膦酸酯的水解动力学拆分为关键步骤，以99％ee作为关键中间体获得对映体二醇。在对相应的膦酸酯进行选择性酯化和脱保护之后，获得对映体均质的（α，α-二氟烷基）膦酸酯。这些化合物是溶血磷脂酸和磷脂酸的新型抗磷酸酶类似物。[反应：看文字]
• Analogs of lysophosphatidic acid and methods of making and using thereof
  申请人：Prestwich D. Glenn

  公开号：US20070123492A1

  公开（公告）日：2007-05-31

  Described herein are analogs of lysophosphatidic acid. Also described herein are methods of making and using analogs of lysophosphatidic acid.

  本文描述了溶血磷脂酸的类似物。本文还描述了制备和使用溶血磷脂酸类似物的方法。
• [EN] ANALOGS OF LYSOPHOSPHATIDIC ACID AND METHODS OF MAKING AND USING THEREOF<br/>[FR] ANALOGUES D'ACIDE LYSOPHOSPHATIDIQUE ET PROCEDES DE LEUR FABRICATION ET DE LEUR UTILISATION
  申请人：UNIV UTAH RES FOUND

  公开号：WO2004092188A3

  公开（公告）日：2005-04-28
• Design, Synthesis, and Evaluation of Phospholipid Analogs as Inhibitors of the Bacterial Phospholipase C from Bacillus cereus
  作者：Stephen F. Martin、Yue-Ling Wong、Allan S. Wagman

  DOI：10.1021/jo00096a024

  日期：1994.8

  Enzymes belonging to the phospholipase C (PLC) family hydrolyze the phosphodiester bond of phospholipids to give a diacylglycerol and a phosphorylated head group. The bacterial phospholipase C from Bacillus cereus (PLC(Bc)) has been studied extensively, and there is a wealth of information regarding those structural features that are important for substrate activity. In contrast, there is virtually no data available regarding structure-activity relationships for inhibitors of this enzyme. To address this shortcoming, a series of optically pure analogues of 1,2-dihexanoyl-sn-glycero-3-phosphocholine (2) containing different replacements of the phosphate group were first synthesized including the phosphoramidates 4 and 8, the phosphonate 5, the (difluoromethylene)phosphonate 6, the thiophosphate 7, the diastereomeric phosphorothioates 9 and 10, and the phosphorodithioate 11. Each of these phosphatidylcholine derivatives was tested for inhibitor or substrate activity with PLC(Bc) using the water-soluble phosphatidylcholine 2 as the monomeric substrate. The measurements were conducted below the critical micellar concentrations of both 2 and the inhibitor. Of the analogues, only 7 and 9 underwent observable enzymatic hydrolysis under the assay conditions used. The k(cat) of the (Sp)-phosphorothioate 9 was approximately one-fifth that of 2, and when compared to 2, 7 was hydrolyzed only very slowly by the enzyme. Kinetic studies indicated that the phospholipid analogues tested were competitive inhibitors with increasing K-i's follows: 7 approximate to 11 approximate to 10 < 4 approximate to 8 < 5 approximate to 6.