(+/-)-(2R,3R,5R)-1-t-butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester | 854986-53-1

• 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: (+/-)-(2R,3R,5R)-1-t-butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester
• 英文别名: ditert-butyl (2R,4R,5R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-formylpyrrolidine-1,2-dicarboxylate
• CAS: 854986-53-1
• 化学式: C₂₂H₄₁NO₆Si
• 分子量: 443.656
• InChiKey: HOBPPNSLILNSMN-BBWFWOEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.54
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+/-)-(2R,3R,5R)-1-t-butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester 在 乙酸铵 、 草酰氯 、 sodium cyanoborohydride 、 二甲基亚砜 、 三乙胺 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 26.5h， 生成 (2S,4S,5S)-5-(1-Amino-3-methyl-butyl)-4-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester
  参考文献：
  名称：

  Structure-Based Characterization and Optimization of Novel Hydrophobic Binding Interactions in a Series of Pyrrolidine Influenza Neuraminidase Inhibitors

  摘要：

  The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.

  DOI：

  10.1021/jm049276y
• 作为产物：
  描述：

  (+/-)-(2R,4R,5R,1'RS)-4-(tert-butyldimethylsilanyloxymethyl)-5-(1',2'-dihydroxyethyl)pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester 在 sodium periodate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 以79%的产率得到(+/-)-(2R,3R,5R)-1-t-butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester
  参考文献：
  名称：

  Structure-Based Characterization and Optimization of Novel Hydrophobic Binding Interactions in a Series of Pyrrolidine Influenza Neuraminidase Inhibitors

  摘要：

  The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.

  DOI：

  10.1021/jm049276y