(-)-(1R,5S)-2-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ethyl ester | 389573-40-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (-)-(1R,5S)-2-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ethyl ester
• 英文别名: (1R)-2-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ethyl ester；ethyl (1R,5S)-2-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate
• CAS: 389573-40-4
• 化学式: C₁₁H₁₄F₃NO₅S
• 分子量: 329.297
• InChiKey: JBHRUJDJLHMDTA-JGVFFNPUSA-N

物化性质

• 沸点：
  379.0±42.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  81.3
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (-)-(1R,5S)-2-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ethyl ester 在 lithium chloride 盐酸 、 copper(l) iodide 、 二(氰基苯)二氯化钯 、 三苯胂 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 (1R)-2-(3'-chloropyrazin-2'-yl)-8-azabicyclo[3.2.1]oct-2-ene
  参考文献：
  名称：

  3D QSAR Analyses-Guided Rational Design of Novel Ligands for the (α4)₂(β2)₃ Nicotinic Acetylcholine Receptor

  摘要：

  Three-dimensional quantitative structure-activity relationship methods, the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA), were applied using a training set of 45 ligands of the (alpha4)(2)(beta2)(3) nicotinic acetylcholine receptor (nAChR). All compounds are related to (-)-epibatidine, (-)-cytisine, (+)-anatoxin-a, and (-)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the same experimental protocol. Statistically reliable models of good predictive power (CoMFA r(2) = 0.928, q(2) = 0.692, no. of components = 3; CoMSIA r(2) = 0.899, q(2) = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field contribution maps. Hence, physicochemical. determinants of binding, such as steric and electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties, were mapped back onto the molecular structures of a set of nAChR modulators. In particular, changes in the binding affinity of the modulators as a result of modifications in the aromatic ring systems could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the rational design of new nAChR ligands such as 48-52 and 54, which were subsequently synthesized for the first time and tested. Key steps of our synthetic approaches were successfully applied Stille and Suzuki cross-coupling reactions. Predictive r(2) values of 0.614 and 0.660 for CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the (alpha4)(2)(beta2)(3) subtype, demonstrate the high quality of the 3D QSAR models.

  DOI：

  10.1021/jm020859m
• 作为产物：
  描述：

  2-[N,正双(三氟甲烷烷磺酰)氨基]-5-氯吡啶 、 (1R,5S)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one 在 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 甲苯 为溶剂， 反应 2.0h， 以85%的产率得到(-)-(1R,5S)-2-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ethyl ester
  参考文献：
  名称：

  Synthesis and evaluation of diazine containing bioisosteres of (−)-ferruginine as ligands for nicotinic acetylcholine receptors

  摘要：

  In this structure-affinity relationship (SAFIR) study, the bioisosteric potential of diazines in the field of ferruginine- type nAChR ligands was investigated. Novel enantiopure analogues of (-)-Ferruginine (3) such as 6 8 were synthesized utilizing enantiomerically pure N-protected (+)-2-tropanone 9 from the 'chiral pool' as versatile chiral building block and a palladium-catalyzed Stille cross-coupling of the tributylstannyl diazines 12, 14 and 16 with the vinyl triflate I I of ( +)-2-tropanone 9. The structures of the novel diazine analogues 6 8 of (-)-ferruginine (3) were assigned on the basis of spectral data, that of ligand 7 being additionally verified by X-ray crystallography. The bioisosteric replacement of the acetyl moiety as structural part of the lead compound 3 with the pyridazine, pyrimidine and pyrazine nucleus resulted in ligands with high to moderate affinity for the central alpha4 beta2 and remarkably low affinity for the alpha7* nAChR subtypes. Among the compounds synthesized and tested, 7 was the most active one with K-i = 3.7 nM (alpha4 beta2). Compared with the lead 3, this value represents a 30-fold improvement in the affinity for the alpha4 beta2 subtype combined with a substantially improved selectivity ratio between the alpha4 beta2 and alpha7* subtypes. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00188-2

文献信息

• Wegge; Schwarz; Seitz, Pharmazie, 2000, vol. 55, # 10, p. 779 - 780
  作者：Wegge、Schwarz、Seitz

  DOI：——

  日期：——
• 3D QSAR Analyses-Guided Rational Design of Novel Ligands for the (α4)₂(β2)₃ Nicotinic Acetylcholine Receptor
  作者：Holger Gohlke、Simone Schwarz、Daniela Gündisch、Maria Cristina Tilotta、Alexander Weber、Thomas Wegge、Gunther Seitz

  DOI：10.1021/jm020859m

  日期：2003.5.1

  Three-dimensional quantitative structure-activity relationship methods, the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA), were applied using a training set of 45 ligands of the (alpha4)(2)(beta2)(3) nicotinic acetylcholine receptor (nAChR). All compounds are related to (-)-epibatidine, (-)-cytisine, (+)-anatoxin-a, and (-)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the same experimental protocol. Statistically reliable models of good predictive power (CoMFA r(2) = 0.928, q(2) = 0.692, no. of components = 3; CoMSIA r(2) = 0.899, q(2) = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field contribution maps. Hence, physicochemical. determinants of binding, such as steric and electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties, were mapped back onto the molecular structures of a set of nAChR modulators. In particular, changes in the binding affinity of the modulators as a result of modifications in the aromatic ring systems could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the rational design of new nAChR ligands such as 48-52 and 54, which were subsequently synthesized for the first time and tested. Key steps of our synthetic approaches were successfully applied Stille and Suzuki cross-coupling reactions. Predictive r(2) values of 0.614 and 0.660 for CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the (alpha4)(2)(beta2)(3) subtype, demonstrate the high quality of the 3D QSAR models.
• Synthesis and evaluation of diazine containing bioisosteres of (−)-ferruginine as ligands for nicotinic acetylcholine receptors
  作者：Daniela Gündisch、Klaus Harms、Simone Schwarz、Gunther Seitz、Milton T Stubbs、Thomas Wegge

  DOI：10.1016/s0968-0896(01)00188-2

  日期：2001.10

  In this structure-affinity relationship (SAFIR) study, the bioisosteric potential of diazines in the field of ferruginine- type nAChR ligands was investigated. Novel enantiopure analogues of (-)-Ferruginine (3) such as 6 8 were synthesized utilizing enantiomerically pure N-protected (+)-2-tropanone 9 from the 'chiral pool' as versatile chiral building block and a palladium-catalyzed Stille cross-coupling of the tributylstannyl diazines 12, 14 and 16 with the vinyl triflate I I of ( +)-2-tropanone 9. The structures of the novel diazine analogues 6 8 of (-)-ferruginine (3) were assigned on the basis of spectral data, that of ligand 7 being additionally verified by X-ray crystallography. The bioisosteric replacement of the acetyl moiety as structural part of the lead compound 3 with the pyridazine, pyrimidine and pyrazine nucleus resulted in ligands with high to moderate affinity for the central alpha4 beta2 and remarkably low affinity for the alpha7* nAChR subtypes. Among the compounds synthesized and tested, 7 was the most active one with K-i = 3.7 nM (alpha4 beta2). Compared with the lead 3, this value represents a 30-fold improvement in the affinity for the alpha4 beta2 subtype combined with a substantially improved selectivity ratio between the alpha4 beta2 and alpha7* subtypes. (C) 2001 Elsevier Science Ltd. All rights reserved.