3-(4-acetylaminophenyl)-4,5-dihydroisoxazole-5-carboxylic acid phenyl ester

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 英文名称: 3-(4-acetylaminophenyl)-4,5-dihydroisoxazole-5-carboxylic acid phenyl ester
• 英文别名: Phenyl 3-(4-acetamidophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate
• 化学式: C₁₈H₁₆N₂O₄
• 分子量: 324.336
• InChiKey: ADPAUQBWOLHUJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  77
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对乙酰氨基苯甲醛 在 羟胺 、 chloroamine-T 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 3-(4-acetylaminophenyl)-4,5-dihydroisoxazole-5-carboxylic acid phenyl ester
  参考文献：
  名称：

  Exploring the Scope of the 29G12 Antibody Catalyzed 1,3-Dipolar Cycloaddition Reaction

  摘要：

  29G12 is a murine monoclonal antibody programmed to catalyze the regio- and enantioselective 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide la and N,N-dimethylacrylamide 2a (Toker, J. D.; Wentworth, P., Jr.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 3244). Given the unique nature of 29G12 as a protein biocatalyst for this chemical reaction, we have investigated both the substrate specificity and mechanistic parameters of the 29G12-catalyzed process. These studies have shown that while 29G12 is specific for its dipole substrate la, the antibody is highly promiscuous with respect to the dipolarophiles it can process. 29G12 accepts a bulky hydrophobic dipolarophile cosubstrate, with rates of product formation up to 70-fold faster than with the original substrate 2a. In all cases, the respective isoxazoline products are produced with exquisite regio- and stereochemical control (78-98% ee). Comparison between the steady-state kinetic parameters from the 29G12-catalyzed reaction of la with the most efficient versus the original dipolarophile cosubstrate (2m and 2a, respectively), reveals that while the effective molarities (EM)s are almost identical (EM(2m) 26 M; EM(2a) 23 M), the affinity of 29G12 for the larger dipolarophile 2m is more than 1 order of magnitude higher than for 2a [K-m(2m) 0.44 +/- 0.04 mM; K-m(2a) 5.8 +/- 0.4 mM]. Furthermore, when 2m is the cosubstrate, the affinity of 29G12 for its dipole la is also greatly improved [K-m(1a) 0.82 +/- 0.1 mM compared to K-m(1a) 3.4 +/- 0.4 mM when 2a is the cosubstrate]. An analysis of the temperature dependence of the 29G12-catalyzed reaction between la and 2m reveals that catalysis is achieved via a decrease in enthalpy of activation (Delta Delta H-double dagger 4.4 kcal mol(-1)) and involves a large increase in the entropy of activation (Delta Delta S-double dagger 10.4 eu). The improved affinity of 29G12 for the nitrile oxide la in the presence of 2m, coupled with the increase in Delta Delta S-double dagger during the 29G12-catalyzed reaction between la and 2m supports the notion of a structural reorganization of the active site to facilitate this antibody-catalyzed reaction.

  DOI：

  10.1021/jo050410b

文献信息

• Exploring the Scope of the 29G12 Antibody Catalyzed 1,3-Dipolar Cycloaddition Reaction
  作者：Jonathan D. Toker、Martin R. Tremblay、Jari Yli-Kauhaluoma、Anita D. Wentworth、Bin Zhou、Paul Wentworth,、Kim D. Janda

  DOI：10.1021/jo050410b

  日期：2005.9.1

  29G12 is a murine monoclonal antibody programmed to catalyze the regio- and enantioselective 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide la and N,N-dimethylacrylamide 2a (Toker, J. D.; Wentworth, P., Jr.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 3244). Given the unique nature of 29G12 as a protein biocatalyst for this chemical reaction, we have investigated both the substrate specificity and mechanistic parameters of the 29G12-catalyzed process. These studies have shown that while 29G12 is specific for its dipole substrate la, the antibody is highly promiscuous with respect to the dipolarophiles it can process. 29G12 accepts a bulky hydrophobic dipolarophile cosubstrate, with rates of product formation up to 70-fold faster than with the original substrate 2a. In all cases, the respective isoxazoline products are produced with exquisite regio- and stereochemical control (78-98% ee). Comparison between the steady-state kinetic parameters from the 29G12-catalyzed reaction of la with the most efficient versus the original dipolarophile cosubstrate (2m and 2a, respectively), reveals that while the effective molarities (EM)s are almost identical (EM(2m) 26 M; EM(2a) 23 M), the affinity of 29G12 for the larger dipolarophile 2m is more than 1 order of magnitude higher than for 2a [K-m(2m) 0.44 +/- 0.04 mM; K-m(2a) 5.8 +/- 0.4 mM]. Furthermore, when 2m is the cosubstrate, the affinity of 29G12 for its dipole la is also greatly improved [K-m(1a) 0.82 +/- 0.1 mM compared to K-m(1a) 3.4 +/- 0.4 mM when 2a is the cosubstrate]. An analysis of the temperature dependence of the 29G12-catalyzed reaction between la and 2m reveals that catalysis is achieved via a decrease in enthalpy of activation (Delta Delta H-double dagger 4.4 kcal mol(-1)) and involves a large increase in the entropy of activation (Delta Delta S-double dagger 10.4 eu). The improved affinity of 29G12 for the nitrile oxide la in the presence of 2m, coupled with the increase in Delta Delta S-double dagger during the 29G12-catalyzed reaction between la and 2m supports the notion of a structural reorganization of the active site to facilitate this antibody-catalyzed reaction.