(2R,3R)-3-O-benzyl-1,2-di-O-isopropylidene-4,4-difluoro-5-hexen-1,2,3-triol | 634181-78-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,3R)-3-O-benzyl-1,2-di-O-isopropylidene-4,4-difluoro-5-hexen-1,2,3-triol
• 英文别名: (R)-4-((R)-1-(benzyloxy)-2,2-difluorobut-3-en-1-yl)-2,2-dimethyl-1,3-dioxolane；(4R)-4-[(1R)-2,2-difluoro-1-phenylmethoxybut-3-enyl]-2,2-dimethyl-1,3-dioxolane
• CAS: 634181-78-5
• 化学式: C₁₆H₂₀F₂O₃
• 分子量: 298.33
• InChiKey: RGXXXAFNDLNUPK-ZIAGYGMSSA-N

物化性质

• 沸点：
  376.6±42.0 °C(Predicted)
• 密度：
  1.115±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  27.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,3R)-3-O-benzyl-1,2-di-O-isopropylidene-4,4-difluoro-5-hexen-1,2,3-triol 在 甲醇 、 三乙基硅烷 、 4-二甲氨基吡啶 、 potassium osmate(VI) dihydrate 、 正丁基锂 、 2,2,6,6-四甲基哌啶氧化物 、 三氯异氰尿酸 、 palladium 10% on activated carbon 、 三氟化硼乙醚 、 四丁基氟化铵 、 氢气 、 四丁基碘化铵 、 sodium hydride 、 二正丁基氧化锡 、 potassium carbonate 、 溶剂黄146 、 甲基磺酰氯 、 N-甲基吗啉氧化物 、 三乙胺 、 邻二氯苯 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 乙酸乙酯 、 丙酮 、 甲苯 、 乙腈 、 mineral oil 为溶剂， 反应 110.5h， 生成 (2S,3R,4R,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol
  参考文献：
  名称：

  Synthesis and biological evaluation of SGLT2 inhibitors: gem-difluoromethylenated Dapagliflozin analogs

  摘要：

  Dapagliflozin is currently the most advanced SGLT2 inhibitor, which has been used in Phase III clinical trials for treatment of diabetes. Here we describe the design and synthesis of Dapagliflozin analogs modified with gem-difluoromethylene group. Their biological evaluation of in vitro inhibitory activity against human SGLT2 showed that some of the analogs with CF2 at C-4 are better SGLT2 inhibitors compared with Dapagliflozin. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2012.02.062
• 作为产物：
  描述：

  (R)-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛 在 四丁基溴化铵 、 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (2R,3R)-3-O-benzyl-1,2-di-O-isopropylidene-4,4-difluoro-5-hexen-1,2,3-triol
  参考文献：
  名称：

  NOVEL STING AGONISTS

  摘要：

  本发明提供了式I′的化合物： 其中 , W, X, Y, Z, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 和R 5 如本文所定义，或其立体异构体、互变异构体、药学上可接受的盐、前药酯或溶剂化合物形式，其中所有变量均如本文所定义。这些化合物能有效调节STING蛋白，因此可用作治疗或预防受STING激动影响的疾病的药物。

  公开号：

  US20200131209A1

文献信息

• NOVEL STING AGONISTS
  申请人：Venenum Biodesign, LLC

  公开号：US20200131209A1

  公开（公告）日：2020-04-30

  The present invention provides compounds of Formula I′: wherein , W, X, Y, Z, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.

  本发明提供了式I′的化合物： 其中 , W, X, Y, Z, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 和R 5 如本文所定义，或其立体异构体、互变异构体、药学上可接受的盐、前药酯或溶剂化合物形式，其中所有变量均如本文所定义。这些化合物能有效调节STING蛋白，因此可用作治疗或预防受STING激动影响的疾病的药物。
• Synthesis of gem-difluorinated nucleoside analogues of the liposidomycins and evaluation as MraY inhibitors
  作者：Xiu-Hua Xu、Amy E. Trunkfield、Timothy D. H. Bugg、Feng-Ling Qing

  DOI：10.1039/b713068f

  日期：——

  Two gem-difluoromethylenated nucleoside moieties of liposidomycins, 3 and 4, were designed and synthesized. Compound 3 was assembled from lactol5 and gem-difluoromethylenated nucleoside6. In the synthesis of target molecule 4, the coupling of the trichloroacetimidate derivative of gem-difluoromethylenated furanose7 with nucleoside8 in the presence of TMSOTf gave the unexpected compound 16 when CH3CN was used as solvent. This results from acetonitrile acting as a nucleophile and participating in the glycosylation reaction. This unusual process may be correlated with the presence of the electron-withdrawing gem-difluoro substituents at the C-2 position of furanose. Compound 3 demonstrated 29% inhibition of MraY at 11.4 mM.

  两种含有gem-二氟亚甲基的核苷部分的脂肪霉素，3和4，进行了设计和合成。化合物3是由醇盐5和gem-二氟亚甲基核苷6组装而成。在目标分子4的合成中，gem-二氟亚甲基呋喃糖7的三氯乙酰亚胺衍生物与核苷8的耦合在TMSOTf的存在下，使用CH3CN作为溶剂时意外产生了化合物16。这是因为乙腈作为亲核试剂参与了糖苷化反应。这一异常过程可能与呋喃糖C-2位置上存在的吸电子gem-二氟取代基有关。化合物3在11.4 mM浓度下对MraY表现出29%的抑制作用。
• Synthesis and conformational analysis of<scp>d</scp>-2′-deoxy-2′,2′-difluoro-4′-dihydro-4′-thionucleosides
  作者：Feng Zheng、Lin Fu、Renxiao Wang、Feng-Ling Qing

  DOI：10.1039/b914679b

  日期：——

  An efficient synthesis of D-2′-deoxy-2′,2′-difluoro-4′-dihydro-4′-thionucleosides is described. The conformations of D-2′-deoxy-2′,2′-difluoro-4′-dihydro-4′-thiouridine were studied by X-ray crystallography, NMR spectroscopy and molecular modeling in an attempt to explore the roles of the two gem-difluorine atoms in the puckering preferences of the thiosugar ring. No matter which conformation (south or north) the thiosugar adopts, there is always one fluorine in a pseudoaxial position, with the other in a pseudoequitorial position and thus the strong antiperiplanar (ap) effects from C–H and C–C σ-bonds to σ*C–F are equal to each other in these two conformers. Therefore, the other weak effects, such as dipole–dipole interactions and electrostatic attractions, become more important for determining the overall conformation of the sugar ring. Based on the results of NMR spectroscopy, high-level quantum computations and molecular dynamic simulations were performed to study the preferred pucker of the thiosugar ring in solution. Our results showed that the strong antiperiplanar preference of C–H and C–C σ-bonds to σ*C–F and σ*C–O seemed to be responsible for the favored S-conformation in solution, and the weak electrostatic attractions between δ+C2–Fβδ− and δ+H6–C6δ- may stabilize the preferred structure further, and keep the base moiety in a high anti-rotamer population in solution. In contrast, the packing forces (hydrogen bond OH⋯OC, dipole–dipole interaction C–F⋯CO) in the solid state compensated the energetic disadvantage of the relatively less stable N-conformation, and drove the thiouridine to crystallize in the N-conformation. These results, along with the earlier empirical rules regarding proton chemical shifts in carbohydrates and nucleosides, were used to propose a method based on proton chemical shifts for the analysis of the N⇌S equilibrium of the fluorinated sugar ring.

  描述了一种高效合成D-2′-脱氧-2′,2′-二氟-4′-氢化-4′-硫核苷的方法。通过X射线晶体学、核磁共振光谱学和分子建模研究了D-2′-脱氧-2′,2′-二氟-4′-氢化-4′-硫尿苷的构象，以探讨两个gem-二氟原子在硫糖环的弯曲偏好中的作用。无论硫糖采用哪种构象（南向或北向），总有一个氟原子处于伪轴向位置，另一个在伪赤道位置，因此C–H和C–C σ键对σ*C–F的强反平面（ap）效应在这两种构象中是相等的。因此，其他弱效应，如偶极-偶极相互作用和静电吸引，在决定糖环的整体构象时变得更加重要。根据核磁共振光谱学的结果，进行高水平量子计算和分子动态模拟以研究溶液中硫糖环的首选弯曲。我们的结果表明，C–H和C–C σ键对σ*C–F和σ*C–O的强反平面偏好似乎是溶液中优选S构象的原因，而δ+C2–Fβδ-和δ+H6–C6δ-之间的弱静电吸引可能进一步稳定了首选结构，并保持基础部分在溶液中较高的反式构象比例。相反，固态中的堆积力（氢键OH¯OC，偶极-偶极相互作用C–F¯CO）弥补了相对不太稳定的N构象的能量劣势，并促使硫尿苷以N构象结晶。这些结果，以及早期关于碳水化合物和核苷中质子化学位移的经验法则，被用于提出一种基于质子化学位移的方法，以分析氟化糖环的N≡S平衡。
• 3-Deoxy-3,3-difluoro-<scp>d</scp>-arabinofuranose:  First Stereoselective Synthesis and Application in Preparation of <i>g</i><i>em</i>-Difluorinated Sugar Nucleosides
  作者：Xingang Zhang、Hairong Xia、XiCheng Dong、Jing Jin、Wei-Dong Meng、Feng-Ling Qing

  DOI：10.1021/jo034512i

  日期：2003.11.1

  The design and synthesis of gem-difluorinated sugar nucleosides were described. The key intermediate, 3-deoxy-3,3-difluoro-d-arabinofuranose 9, was first stereoselectively prepared from the chiral gem-difluorohomoallyl alcohol 12. The kinetic formation of single anti-14 in the benzylation of 12 could be accomplished by controlling the amount of sodium hydride used. The dihydroxylation of 14 (a mixture

  描述了宝石二氟化糖核苷的设计与合成。关键的中间体3-脱氧-3,3-二氟-d-阿拉伯呋喃糖9首先是从手性的gem-difluorohomoallyl醇12立体选择性地制备的。可以通过控制12的苄基化反应来实现单一抗14的动力学形成。氢化钠的用量。14（反异构体和顺式异构体的混合物）的二羟基化，然后脱保护和立体氧化，选择性地得到在C2位具有阿拉伯糖构型的呋喃糖9。由9通过糖基化反应制备N（1）-（3-脱氧-3,3-二氟-β-D-阿拉伯呋喃糖基）胞嘧啶6。4'-硫呋喃糖25很容易从9合成。25的氧化，然后与甲硅烷基化的N（4）-苯甲酰胞嘧啶缩合（Pummerer反应）未能得到我们所需要的受保护的核苷1'3'-脱氧3'，3'-二氟-4'-硫代胞嘧啶核苷27'，但得到区域异构体27。Pummerer反应的区域化学由4'-硫呋喃糖25的α-质子的动力学酸性确定。
• Sting agonists
  申请人：Venenum Biodesign, LLC

  公开号：US11161864B2

  公开（公告）日：2021-11-02

  The present invention provides compounds of Formula I′: wherein , W, X, Y, Z, Z1, Z2, R1, R2, R3, R4 and R5 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.

  本发明提供了式 I′的化合物： 其中 ，W、X、Y、Z、Z1、Z2、R1、R2、R3、R4和R5如本文所定义，或其立体异构体、同分异构体、药学上可接受的盐、原药酯或溶胶形式，其中所有变量如本文所定义。这些化合物能有效调节 STING 蛋白，因此可用作治疗或预防受 STING 激动作用影响的疾病的药物。