(1R,5S)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one | 281650-60-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: (1R,5S)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one
• 英文别名: (+)-(1R)-2-oxo-tropane-8-carboxylic acid ethyl ester；ethyl (1R,5S)-2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate
• CAS: 281650-60-0
• 化学式: C₁₀H₁₅NO₃
• 分子量: 197.234
• InChiKey: PEMNIGBMAQWXIG-JGVFFNPUSA-N

物化性质

• 沸点：
  311.3±25.0 °C(Predicted)
• 密度：
  1.198±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1R,5S)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one 在 lithium chloride copper(l) iodide 、 二(氰基苯)二氯化钯 、 碘代三甲硅烷 、 三苯胂 作用下， 以 N-甲基吡咯烷酮 、 氯仿 为溶剂， 反应 18.75h， 生成 (1R)-2-(4-pyridazinyl)-8-azabicyclo[3.2.1]oct-2-ene
  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
• 作为产物：
  描述：

  (5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-one 、 氯甲酸乙酯 在 potassium carbonate 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以98%的产率得到(1R,5S)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one
  参考文献：
  名称：

  顺式-吡咯烷 225H 两种对映体的对映选择性合成

  摘要：

  两栖生物碱顺式-225H的两种对映异构体的高效和快速合成已经实现。利用衍生自 (+)-2-tropinone的常见顺式-2,5-二取代吡咯烷结构单元，对映选择性合成已确定这些生物碱的绝对构型为 (+)-(2 R ,5 S ) 和 (-) -(5 S ,2 R )。

  DOI：

  10.1016/j.tet.2010.04.037

文献信息

• Syntheses and evaluation of pyridazine and pyrimidine Containing bioisosteres of (±)-Pyrido[3.4-b]homotropane and Pyrido-[3.4-b]tropane as novel nAChR ligands
  作者：Daniela Gündisch、Thomas Kämpchen、Simone Schwarz、Gunther Seitz、Johanna Siegl、Thomas Wegge

  DOI：10.1016/s0968-0896(01)00258-9

  日期：2002.1

  (+)-anatoxin-a (1), replacement of the pyridine by the bioisosteric pyridazine resulted in 30-fold lower affinity at the (alpha4)2(beta2)3 subtype. The annulated diazinotropanes 6-8, ligands with ferruginine-like structures more or less retained the affinity of (-)-norferruginine (3) except of compound 7. Remarkably, all of the novel ligands are devoid of affinity at the alpha7* subtype.

  用哒嗪和嘧啶核生物置换（+/-）-吡啶并[3.4-b]高托烷（PHT）和吡啶[3.4-b]托烷中的吡啶药效成分导致迄今未知的nAChR配体，如5-8。逆型Diels-Alder反应构成了通往哒嗪或嘧啶环化的生物等位基因新路线的关键步骤。来自“手性库”的对映体纯（+）-2-托宁酮（11）被转化为扩环的甲硅烷基烯醇醚12和烯胺15。两者均被证明是逆型[4 + 2与1,2,4,5-四嗪13和16a，b或与1,3,5-三嗪19的环加成反应以提供对映纯的目标化合物5-7。以相同的方式从3-对pan酮21获得外消旋嘧啶环化的物质8。测试了新的配体在体外对（alpha4）2（beta2）3和alpha7 * nAChR亚型的亲和力。与众所周知对大鼠脑中激动剂结合位点表现出亲和力的PHT（约）（+）-毒素（a）相比，生物等位哒嗪取代吡啶导致的亲和力降低30倍。 （alpha4）2（beta2）3亚型。除了
• A new and efficient synthetic route to enantiopure (+)-anatoxin-a from (−)-cocaine hydrochloride
  作者：Thomas Wegge、Simone Schwarz、Gunther Seitz

  DOI：10.1016/s0957-4166(00)00059-8

  日期：2000.4

  The potent nAChR agonist (+)-anatoxin-a was efficiently synthesized in enantiomerically pure form starting from a readily available confiscated grade (-)-cocaine hydrochloride. The eight-step synthesis providing novel extensions to existing methodology proceeded with 26% overall yield and with stereochemical integrity of the relevant original stereogenic centers. Key steps were an effective ring expansion of the (+)-2-tropinone 2 to the 9-azabicyclo[4.2.1]nonanone 5 with TMSCHN2/Al(CH3)(3) and the introduction of the required methyl ketone side chain in masked form by reacting the corresponding enol triflate 6 with ethyl vinyl ether/Pd(OAc2) under Heck reaction conditions. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Wegge; Schwarz; Seitz, Pharmazie, 2000, vol. 55, # 10, p. 779 - 780
  作者：Wegge、Schwarz、Seitz

  DOI：——

  日期：——
• Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H
  作者：Hong Shu、April R. Noble、Suhong Zhang、Lei Miao、Mark L. Trudell

  DOI：10.1016/j.tet.2010.04.037

  日期：2010.6

  The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+)-(2R,5S) and (−)-(5S,2R).

  两栖生物碱顺式-225H的两种对映异构体的高效和快速合成已经实现。利用衍生自 (+)-2-tropinone的常见顺式-2,5-二取代吡咯烷结构单元，对映选择性合成已确定这些生物碱的绝对构型为 (+)-(2 R ,5 S ) 和 (-) -(5 S ,2 R )。
• 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.