(3aR,9bS)-1-Benzoyl-2-(2,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-2H-naphtho[1,2-d]oxazole-3a-carboxylic acid | 1026039-16-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (3aR,9bS)-1-Benzoyl-2-(2,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-2H-naphtho[1,2-d]oxazole-3a-carboxylic acid
• 英文别名: (3aR,9bS)-1-benzoyl-2-(2,4-dimethoxyphenyl)-2,4,5,9b-tetrahydrobenzo[e][1,3]benzoxazole-3a-carboxylic acid
• CAS: 1026039-16-6
• 化学式: C₂₇H₂₅NO₆
• 分子量: 459.499
• InChiKey: MKKXVTHVYQPDMB-BQAPZBJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  85.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (3aR,9bS)-1-Benzoyl-2-(2,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-2H-naphtho[1,2-d]oxazole-3a-carboxylic acid 在 盐酸 、 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 甲苯 为溶剂， 反应 7.0h， 生成 [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-2-benzoyloxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-15-yl] (1S,2R)-1-benzamido-2-hydroxy-3,4-dihydro-1H-naphthalene-2-carboxylate
  参考文献：
  名称：

  Synthesis and NMR-Driven Conformational Analysis of Taxol Analogues Conformationally Constrained on the C13 Side Chain

  摘要：

  Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2 ' -carbon and the ortho-position of the 3 ' -phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2 ' and C3 '. Two analogues in the home series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta -tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2 ' and C3 ' and (2) an orthogonal arrangement of the mean plane through C1 ', C2 ' and the 2 ' -hydroxyl and the 3 ' -phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2 ' ,3 ' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.

  DOI：

  10.1021/jm001103v
• 作为产物：
  描述：

  3,4-Dihydronaphthalin-2-carbonsaeure-ethylester 在 palladium on activated charcoal 吡啶 、 ruthenium trichloride 、 sodium periodate 、 AD-mix-α 、 氯化亚砜 、 sodium azide 、 四丁基溴化铵 、 水 、 氢气 、 4-甲基苯磺酸吡啶 、 碳酸氢钠 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 乙腈 、 叔丁醇 为溶剂， 50.0 ℃ 、101.33 kPa 条件下， 反应 12.09h， 生成 (3aR,9bS)-1-Benzoyl-2-(2,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-2H-naphtho[1,2-d]oxazole-3a-carboxylic acid
  参考文献：
  名称：

  Synthesis and NMR-Driven Conformational Analysis of Taxol Analogues Conformationally Constrained on the C13 Side Chain

  摘要：

  Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2 ' -carbon and the ortho-position of the 3 ' -phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2 ' and C3 '. Two analogues in the home series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta -tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2 ' and C3 ' and (2) an orthogonal arrangement of the mean plane through C1 ', C2 ' and the 2 ' -hydroxyl and the 3 ' -phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2 ' ,3 ' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.

  DOI：

  10.1021/jm001103v

文献信息

• Synthesis and NMR-Driven Conformational Analysis of Taxol Analogues Conformationally Constrained on the C13 Side Chain
  作者：Luciano Barboni、Catia Lambertucci、Giovanni Appendino、David G. Vander Velde、Richard H. Himes、Ezio Bombardelli、Minmin Wang、James P. Snyder

  DOI：10.1021/jm001103v

  日期：2001.5.1

  Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2 ' -carbon and the ortho-position of the 3 ' -phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2 ' and C3 '. Two analogues in the home series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta -tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2 ' and C3 ' and (2) an orthogonal arrangement of the mean plane through C1 ', C2 ' and the 2 ' -hydroxyl and the 3 ' -phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2 ' ,3 ' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.