2-<(4-dimethoxyphosphinyl)-3-oxobutyl>-4-methylphenol | 154596-79-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 2-<(4-dimethoxyphosphinyl)-3-oxobutyl>-4-methylphenol
• CAS: 154596-79-9
• 化学式: C₁₃H₁₉O₅P
• 分子量: 286.265
• InChiKey: LMCSOWOCPNZCRT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.69
• 重原子数：
  19.0
• 可旋转键数：
  7.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  72.83
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-<(4-dimethoxyphosphinyl)-3-oxobutyl>-4-methylphenol 在 palladium on activated charcoal 三乙基硅烷 、 草酰氯 、 dowex 、 三氟化硼乙醚 、 硼烷 、 lithium 、 氢气 、 四氯化钛 、 碳酸氢钠 、 potassium hydrogencarbonate 、 叔丁胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 硝基甲烷 、 二氯甲烷 为溶剂， 反应 113.5h， 生成
  参考文献：
  名称：

  Structure-Based Design of an Inhibitor of the Zinc Peptidase Thermolysin

  摘要：

  The full cycle of design, synthesis, and enzymatic and crystallographic evaluation of a structure-based inhibitor of thermolysin is described. Using the structure of the complex of thermolysin with Cbz-Gly(P)-Leu-Leu (K-i = 9 nM; ''Gly(P)'' = NHCH2PO2-) as the starting point, we designed the macrocyclic phosphonamidate (S,S)-1 as a conformationally constrained derivative. The chroman linking unit was designed to rigidify the peptide analog while avoiding unfavorable steric interactions with the enzyme. (S,S)-1 was synthesized by a route that provided all of the stereoisomers in pure form; the acyclic control compounds 2 and 3 were also prepared. The binding affinity of (S,S)-1 (K-i = 4 nM) is enhanced by 2.3 kcal/mol in comparison to 3 (K-i = 190 nM); the other diastereomers of 1 are considerably less potent (K-i greater than or equal to 500 nM). Crystallographic analysis of the complexes between thermolysin and (S,S)-1 and (S)-2 demonstrated that the anticipated mode of binding of (S,S)-1 was fundamentally correct, while revealing some discrepancies with the original model. The structural studies also showed that the chroman moiety in the acyclic analog (S)-2 binds in a different orientation than in the macrocycle, an observation that is important for interpreting the differences in affinity between the macrocyclic inhibitor and the control compounds.

  DOI：

  10.1021/ja00087a010
• 作为产物：
  描述：

  3,4-二氢-6-甲基-2H-1-苯并吡喃-2-酮 、 甲基膦酸二甲酯 在 lithium diisopropyl amide 作用下， 生成 2-<(4-dimethoxyphosphinyl)-3-oxobutyl>-4-methylphenol
  参考文献：
  名称：

  Structure-Based Design of an Inhibitor of the Zinc Peptidase Thermolysin

  摘要：

  The full cycle of design, synthesis, and enzymatic and crystallographic evaluation of a structure-based inhibitor of thermolysin is described. Using the structure of the complex of thermolysin with Cbz-Gly(P)-Leu-Leu (K-i = 9 nM; ''Gly(P)'' = NHCH2PO2-) as the starting point, we designed the macrocyclic phosphonamidate (S,S)-1 as a conformationally constrained derivative. The chroman linking unit was designed to rigidify the peptide analog while avoiding unfavorable steric interactions with the enzyme. (S,S)-1 was synthesized by a route that provided all of the stereoisomers in pure form; the acyclic control compounds 2 and 3 were also prepared. The binding affinity of (S,S)-1 (K-i = 4 nM) is enhanced by 2.3 kcal/mol in comparison to 3 (K-i = 190 nM); the other diastereomers of 1 are considerably less potent (K-i greater than or equal to 500 nM). Crystallographic analysis of the complexes between thermolysin and (S,S)-1 and (S)-2 demonstrated that the anticipated mode of binding of (S,S)-1 was fundamentally correct, while revealing some discrepancies with the original model. The structural studies also showed that the chroman moiety in the acyclic analog (S)-2 binds in a different orientation than in the macrocycle, an observation that is important for interpreting the differences in affinity between the macrocyclic inhibitor and the control compounds.

  DOI：

  10.1021/ja00087a010