(1R,2S,4R,5S)-(2-acetoxy-4-hydroxybicyclo[3.1.0]hex-1-yl)methyl acetate | 452335-24-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (1R,2S,4R,5S)-(2-acetoxy-4-hydroxybicyclo[3.1.0]hex-1-yl)methyl acetate
• 英文别名: acetic acid 2-acetoxy-4-hydroxy-bicyclo[3.1.0]hex-1-ylmethyl ester；acetic acid 1-acetoxymethyl-4-hydroxybicyclo[3.1.0]hex-2-yl ester；[(1R,2S,4R,5S)-2-acetyloxy-4-hydroxy-1-bicyclo[3.1.0]hexanyl]methyl acetate
• CAS: 452335-24-9
• 化学式: C₁₁H₁₆O₅
• 分子量: 228.245
• InChiKey: QCRFMJRSHAAINZ-ZNSHCXBVSA-N

物化性质

• 沸点：
  300.2±12.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1R,2S,4R,5S)-(2-acetoxy-4-hydroxybicyclo[3.1.0]hex-1-yl)methyl acetate 在 四氮唑 、 4-二甲氨基吡啶 、 偶氮二甲酸二异丙酯 、 四丁基氟化铵 、 potassium carbonate 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 145.0h， 生成 (1'R,2'S,4'S,5'S)-phosphoric acid di-tert-butyl ester 1-(di-tert-butoxy-phosphoryloxymethyl)-4-(6-chloro-2-iodo-purin-9-yl)-bicyclo[3.1.0]hex-2-yl ester
  参考文献：
  名称：

  Antiaggregatory activity in human platelets of potent antagonists of the P2Y1 receptor

  摘要：

  Activation of the P2Y(1) nucleotide receptor in platelets by ADP causes changes in shape and aggregation, mediated by activation of phospholipase C (PLC). Recently, MRS2500 (2-iodo-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate) was introduced as a highly potent and selective antagonist for this receptor. We have studied the actions of MRS2500 in human platelets and compared these effects with the effects of two acyclic nucleotide analogues, a bisphosphate MRS2298 and a bisphosphonate derivative MRS2496, which act as P2Y(1) receptor antagonists, although less potently than MRS2500. Improved synthetic methods for MRS2500 and MRS2496 were devised. The bisphosphonate is predicted to be more stable in general in biological systems than phosphate antagonists due to the non-hydrolyzable C-P bond. MRS2500 inhibited the ADP-induced aggregation of human platelets with an IC50 value of 0.95 nM. MRS2298 and MRS2496 also both inhibited the ADP-induced aggregation of human platelets with IC50 values of 62.8 nM and 1.5 muM, respectively. A similar order of potency was observed for the three antagonists in binding to the recombinant human P2Y(1) receptor and in inhibition of ADP-induced shape change and ADP-induced rise in intracellular Ca2+. No substantial antagonism of the pathway linked to the inhibition of cyclic AMP was observed for the nucleotide derivatives, indicating no interaction of these three P2Y(1) receptor antagonists with the proaggregatory P2Y(12) receptor, which is also activated by ADP. Thus, all three of the bisphosphate derivatives are highly selective antagonists of the platelet P2Y(1) receptor, and MRS2500 is the most potent such antagonist yet reported. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2004.06.026
• 作为产物：
  描述：

  (1R,2S,4R,5S)-[2-acetoxy-4-(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)bicyclo[3.1.0]hex-1-yl]methyl acetate 在 氟化铵 作用下， 以 甲醇 为溶剂， 反应 12.0h， 生成 (1R,2S,4R,5S)-(2-acetoxy-4-hydroxybicyclo[3.1.0]hex-1-yl)methyl acetate
  参考文献：
  名称：

  通过脂肪酶催化的不对称乙酰化反应，对映选择性地合成双环[3.1.0]己烷碳环核苷。异常乙缩醛副产物的表征。

  摘要：

  双环[3.1.0]己烷骨架可将碳环核苷的构型锁定为通常在溶液中以快速，两态平衡存在的常规核苷典型的两个对映体（北或南）构型之一。在最近的简短交流中，我们报道了一种通过分子内烯烃-酮卡宾环加成反应获得对映体所需的双环[3.1.0]己烷假糖的实用方法。该合成法最吸引人的特征是，可以从简单且廉价的起始原料中获得相对复杂的合成子，并且嘌呤核苷的外消旋混合物可以通过腺苷脱氨酶（ADA）水解成功分离。在这项工作中，我们描述了一种更普遍的脂肪酶催化双乙酰化反应的发展，可以成功地将较早的前体4-（叔丁基二苯基硅甲氧基）-1-（羟甲基）双环[3.1.0]己-2-醇[（+/-）-7]拆分为对映体纯的（+）-二乙酸酯8和（-）-单乙酸酯9。原来的双乙酸酯被转化为构象锁定的（北）-碳环鸟苷（+）-17，与先前通过ADA解析得到的相同。本方法代表了适用于合成所有类型的（北）双环[3.1.0]己烷核苷，包括嘧啶类似物

  DOI：

  10.1021/jo020249u

文献信息

• Convergent or Linear? A Challenging Question in Carbocyclic Nucleoside Chemistry
  作者：Victor Marquez、Olaf Ludek

  DOI：10.1055/s-2007-990847

  日期：2007.11

  dine (N-MCT) is a carbocyclic nucleoside analogue with potent anti-HSV and KSHV activity. The critical step in the synthesis of N-MCT and other carbocyclic nucleoside analogues is the introduction of the nucleobase into the carbocyclic moiety. For this, convergent and linear strategies were compared side by side. In the convergent approach, the base was coupled to the carbocyclic moiety by either a

  North-methanocarbathymidine (N-MCT) 是一种碳环核苷类似物，具有有效的抗 HSV 和 KSHV 活性。合成 N-MCT 和其他碳环核苷类似物的关键步骤是将核碱基引入碳环部分。为此，并排比较了收敛策略和线性策略。在收敛方法中，碱基通过光信反应或甲磺酸酯的置换与碳环部分偶联。该策略导致形成不同量的O 2 -区域异构体，这取决于所应用的程序。此外，Mitsunobu 反应的副产物必须从偶联产物中分离出来。虽然更长，但线性策略选择性地导致目标化合物 N-MCT，总产率与收敛方法相当，
• Synthesis and Conformational Analysis of Locked Carbocyclic Analogues of 1,3-Diazepinone Riboside, a High-Affinity Cytidine Deaminase Inhibitor
  作者：Olaf R. Ludek、Gottfried K. Schroeder、Chenzhong Liao、Pamela L. Russ、Richard Wolfenden、Victor E. Marquez

  DOI：10.1021/jo901127a

  日期：2009.8.21

  site. Nucleoside analogues where the leaving NH3 group is replaced by a proton and prevent conversion of the transition state to product are very potent inhibitors of the enzyme. However, stable carbocyclic versions of these analogues are less effective as the role of the ribose in facilitating formation of hydrated species is abolished. The discovery that a 1,3-diazepinone riboside (4) operated as a

  胞苷脱氨酶 (CDA) 通过由锌结合水在活性位点的亲核攻击产生的水合过渡态中间体催化胞苷脱氨。离开的NH 3基团被质子取代并防止过渡态转化为产物的核苷类似物是非常有效的酶抑制剂。然而，这些类似物的稳定碳环形式不太有效，因为核糖在促进水合物种形成方面的作用被取消。发现 1,3-二氮杂酮核苷 ( 4) 作为 CDA 的紧密结合抑制剂，独立于水合作用，为研究构建为构象锁定的碳环 1,3-二氮杂酮核苷的新型抑制剂提供了机会，以确定酶对特定形式的糖褶的构象偏好。这项工作描述了两个目标双环 [3.1.0] 己烷核苷的合成，锁定为北 ( 5 ) 和南 ( 6 ) 构象异构体，以及一个灵活的类似物 ( 7) 由环戊烷环构成。所有三个目标中的七元 1,3-二氮杂环酮环是通过闭环复分解由相应的苯甲酰基保护的碳环双烯丙基脲构建的。结果表明 CDA 对南糖褶皱的结合偏好与结合在活性位点的其他 CDA 抑制剂的高分辨率晶体结构一致。
• Recent Advances in the Synthesis of Conformationally Locked Nucleosides and Their Success in Probing the Critical Question of Conformational Preferences by Their Biological Targets
  作者：Yongseok Choi、Hyung R. Moon、Yuichi Yoshimura、Victor E. Marquez

  DOI：10.1081/ncn-120021954

  日期：2003.10

  The present work describes some recent approaches to the syntheses of three classes of locked-North nucleosides: beta-D-ribo-, beta-D-deoxyribo-, and beta-D-dideoxy-ribonucleosides. The method developed for the latter class permitted access to a novel bicyclo[3.1.0]hexene-type nucleosides structurally similar to D4T and carbovir. A structural analysis and biological activities are discussed.
• P2Y₁ Antagonists:  Combining Receptor-Based Modeling and QSAR for a Quantitative Prediction of the Biological Activity Based on Consensus Scoring
  作者：Stefano Costanzi、Irina G. Tikhonova、Michihiro Ohno、Eun Joo Roh、Bhalchandra V. Joshi、Anny-Odile Colson、Dayle Houston、Savitri Maddileti、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm0700971

  日期：2007.7.1

  P2Y(1) is an ADP-activated G protein-coupled receptor (GPCR). Its antagonists impede platelet aggregation in vivo and are potential antithrombotic agents. Combining ligand and structure-based modeling we generated a consensus model (LIST-CM) correlating antagonist structures with their potencies. We docked 45 antagonists into our rhodopsin-based human P2Y(1) homology model and calculated docking scores and free binding energies with the Linear Interaction Energy (LIE) method in continuum-solvent. The resulting alignment was also used to build QSAR based on CoMFA, CoMSIA, and molecular descriptors. To benefit from the strength of each technique and compensate for their limitations, we generated our LIST-CM with a PLS regression based on the predictions of each methodology. A test set featuring untested substituents was synthesized and assayed in inhibition of 2-MeSADP-stimulated PLC activity and in radioligand binding. LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set.