(R)-((4aS,5aR,6R,8aS,8bS)-6-(benzylcarbamoyl)-5a-((Z)-2-((tert-butoxycarbonyl)oxy)vinyl)-1-((2-nitrophenyl)sulfonyl)-8-oxo-5a,6,8,8a-tetrahydro-1H-pyrrolo[3',4':4,5]furo[3,2-b]pyridin-7(2H,4aH,8bH)-yl)-2-(4-methoxyphenyl)ethyl acetate | 1427207-84-8

• 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: (R)-((4aS,5aR,6R,8aS,8bS)-6-(benzylcarbamoyl)-5a-((Z)-2-((tert-butoxycarbonyl)oxy)vinyl)-1-((2-nitrophenyl)sulfonyl)-8-oxo-5a,6,8,8a-tetrahydro-1H-pyrrolo[3',4':4,5]furo[3,2-b]pyridin-7(2H,4aH,8bH)-yl)-2-(4-methoxyphenyl)ethyl acetate
• 英文别名: [(2R)-2-[(1S,2S,5R,6R,8S)-5-(benzylcarbamoyl)-6-[(Z)-2-[(2-methylpropan-2-yl)oxycarbonyloxy]ethenyl]-12-(2-nitrophenyl)sulfonyl-3-oxo-7-oxa-4,12-diazatricyclo[6.4.0.02,6]dodec-9-en-4-yl]-2-(4-methoxyphenyl)ethyl] acetate
• CAS: 1427207-84-8
• 化学式: C₄₁H₄₄N₄O₁₃S
• 分子量: 832.885
• InChiKey: OKDRFKRHBICQJO-YVEQVITMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  59
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  221
• 氢给体数：
  1
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  2-((4aS,5aR,6R,8aS,8bS)-7-((R)-2-acetoxy-1-(4-methoxyphenyl)ethyl)-6-(benzyl(tert-butoxycarbonyl)carbamoyl)-1-((2-nitrophenyl)sulfonyl)-8-oxo-2,4a,5a,6,7,8,8a,8b-octahydro-1H-pyrrolo[3',4':4,5]furo[3,2-b]pyridin-5a-yl)vinyl acetate 、 三甲基硅烷化重氮甲烷 在 potassium carbonate 、 sodium chlorite 、 sodium dihydrogenphosphate 作用下， 以 甲醇 、 四氢呋喃 、 水 为溶剂， 反应 5.5h， 以20%的产率得到(4aS,5aR,6R,8aS,8bS)-methyl 7-((R)-2-acetoxy-1-(4-methoxyphenyl)ethyl)-5a-(2-methoxy-2-oxoethyl)-1-((2-nitrophenyl)sulfonyl)-8-oxo-2,4a,5a,6,7,8,8a,8b-octahydro-1H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6-carboxylate
  参考文献：
  名称：

  Studies on an (S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

  摘要：

  IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.

  DOI：

  10.1021/jm301590z