N-(cyclopropylmethyl)-6,14-endo-etheno-7α-(3-carboxy-3-n-butenyl)tetrahydronororipavine γ-lactone | 127154-03-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: N-(cyclopropylmethyl)-6,14-endo-etheno-7α-(3-carboxy-3-n-butenyl)tetrahydronororipavine γ-lactone
• 英文别名: (5R)-5-[(1R,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-11-hydroxy-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11,18-tetraen-16-yl]-3-methylideneoxolan-2-one
• CAS: 127154-03-4
• 化学式: C₂₈H₃₁NO₅
• 分子量: 461.558
• InChiKey: OZWOAKUHWIGMQA-IXUQSROBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  68.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-O-(tert-butyldimethylsilyl)-N-(cyclopropylmethyl)-6,14-endo-etheno-7α-formyltetrahydronororipavine 在 四丁基氟化铵 、 锌 作用下， 以 四氢呋喃 为溶剂， 反应 7.17h， 生成 N-(cyclopropylmethyl)-6,14-endo-etheno-7α-(3-carboxy-3-n-butenyl)tetrahydronororipavine γ-lactone
  参考文献：
  名称：

  Electrophilic .alpha.-methylene-.gamma.-lactone and isothiocyanate opioid ligands related to etorphine

  摘要：

  Isothiocyanate and alpha-methylene-gamma-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7 alpha-side chain. Isothiocyanates were prepared in the N-Me and N-CPM (N-cyclopropylmethyl) series, both as the phenols and 3-O-methyl ethers from the diastereomeric amines formed from reductive amination of thevinone (2) and N-(cyclopropylmethyl)northevinone (13). Although addition of the organozinc reagent from methyl alpha-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, alpha-methylene-gamma-lactones 29 and 37, respectively. In the opioid receptor displacement assays against [3H]bremazocine as the radiolabeled ligand, the phenolic compounds were most potent with N-CPM isothiocyanates 20 and 21 showing IC50s of 0.32 and 0.76 nM, respectively, and N-CPM alpha-methylene-gamma-lactone 37 having an IC50 = 1.0 nM. Compound 37 showed irreversible effects in the binding assay which were mu-selective, as demonstrated by analogous experiments using [3H]DAGO, and naloxone was found to protect against the irreversible effects. This observation suggests that a receptor-bound nucleophile is located at a position where it can readily reach the alpha-methylene group of lactone 37.

  DOI：

  10.1021/jm00170a038

文献信息

• Electrophilic .alpha.-methylene-.gamma.-lactone and isothiocyanate opioid ligands related to etorphine
  作者：Peter Klein、Wendel L. Nelson、Yi He Yao、Eric J. Simon

  DOI：10.1021/jm00170a038

  日期：1990.8

  Isothiocyanate and alpha-methylene-gamma-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7 alpha-side chain. Isothiocyanates were prepared in the N-Me and N-CPM (N-cyclopropylmethyl) series, both as the phenols and 3-O-methyl ethers from the diastereomeric amines formed from reductive amination of thevinone (2) and N-(cyclopropylmethyl)northevinone (13). Although addition of the organozinc reagent from methyl alpha-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, alpha-methylene-gamma-lactones 29 and 37, respectively. In the opioid receptor displacement assays against [3H]bremazocine as the radiolabeled ligand, the phenolic compounds were most potent with N-CPM isothiocyanates 20 and 21 showing IC50s of 0.32 and 0.76 nM, respectively, and N-CPM alpha-methylene-gamma-lactone 37 having an IC50 = 1.0 nM. Compound 37 showed irreversible effects in the binding assay which were mu-selective, as demonstrated by analogous experiments using [3H]DAGO, and naloxone was found to protect against the irreversible effects. This observation suggests that a receptor-bound nucleophile is located at a position where it can readily reach the alpha-methylene group of lactone 37.