(1'R,2'S,4'R,5'S)-4-(tert-butyl-diphenylsilanyloxy)-1-hydroxymethyl-bicyclo[3.1.0]hexan-2-ol | 404577-47-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1'R,2'S,4'R,5'S)-4-(tert-butyl-diphenylsilanyloxy)-1-hydroxymethyl-bicyclo[3.1.0]hexan-2-ol
• CAS: 404577-47-5
• 化学式: C₂₃H₃₀O₃Si
• 分子量: 382.575
• InChiKey: LHUSGTKYSBGQPO-JFYQVNSESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.69
• 重原子数：
  27.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  49.69
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (1'R,2'S,4'R,5'S)-4-(tert-butyl-diphenylsilanyloxy)-1-hydroxymethyl-bicyclo[3.1.0]hexan-2-ol 在 四氮唑 、 偶氮二甲酸二异丙酯 、 四丁基氟化铵 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 50.0h， 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 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 72.0h， 以1.24 g的产率得到(1'R,2'S,4'R,5'S)-4-(tert-butyl-diphenylsilanyloxy)-1-hydroxymethyl-bicyclo[3.1.0]hexan-2-ol
  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

文献信息

• Enantioselective Synthesis of Bicyclo[3.1.0]hexane Carbocyclic Nucleosides via a Lipase-Catalyzed Asymmetric Acetylation. Characterization of an Unusual Acetal Byproduct
  作者：Yuichi Yoshimura、Hyung R. Moon、Yongseok Choi、Victor E. Marquez

  DOI：10.1021/jo020249u

  日期：2002.8.1

  The bicyclo[3.1.0]hexane scaffold can lock the conformation of a carbocyclic nucleoside into one of the two antipodal (north or south) conformations typical of conventional nucleosides that normally exist in a rapid, two-state equilibrium in solution. In a recent brief communication, we reported a practical method to access the requisite bicyclo[3.1.0]hexane pseudosugar for the north antipode via an

  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