(S)-1-(4-bromophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (S)-1-(4-bromophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one
• 英文别名: (5S)-1-(4-bromophenyl)-5-tert-butyldimethylsilyloxymethyl-2-pyrrolidinone；(5S)-1-(4-bromophenyl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one
• 化学式: C₁₇H₂₆BrNO₂Si
• 分子量: 384.388
• InChiKey: MNMNXXZHDOMIBU-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.97
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (S)-1-(4-bromophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 四丁基氟化铵 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 N,N-二甲基甲酰胺 、 三氟乙酸 为溶剂， -78.0~100.0 ℃ 、344.75 kPa 条件下， 反应 162.0h， 生成 ((2S,5S)-5-methyl-1-(4-(2-methylbenzyl)phenyl)pyrrolidin-2-yl)methanol
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

  DOI：

  10.1021/acs.jmedchem.6b01559
• 作为产物：
  描述：

  1,4-二溴苯 、 (S)-5-(((叔丁基二甲基甲硅烷基)氧基)甲基)吡咯烷-2-酮 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 为溶剂， 反应 18.0h， 以62%的产率得到(S)-1-(4-bromophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one
  参考文献：
  名称：

  Synthesis of chiral N -aryl pyrrolidinones via a palladium-catalyzed cross-coupling reaction

  摘要：

  The direct synthesis of non-racemic N-aryl pyrrolidinones through the application of the Buchwald/Hartwig aryl amination reaction is reported. These reactions proceed in generally good yield, with a variety of electron deficient aryl bromides and with retention of stereochemical purity. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(01)01501-5

文献信息

• Palladium-catalyzed aryl-amidation. Synthesis of non-racemic N-aryl lactams
  作者：R.Greg Browning、Vivek Badarinarayana、Hossen Mahmud、Carl J Lovely

  DOI：10.1016/j.tet.2003.11.008

  日期：2004.1

  The Buchwald/Hartwig aryl amination method was used to construct a series of chiral, non-racemic N-aryl pyrrolidinones from a common pyrrolidinone precursor and the corresponding aryl bromide. The stereochemical integrity of the N-aryl lactam after cross-coupling was proven by synthesis of the racemic compounds and comparison by H-1 NMR spectroscopy using Pirkle's chiral solvating agent. (C) 2003 Elsevier Ltd. All rights reserved.
• Synthesis of chiral N -aryl pyrrolidinones via a palladium-catalyzed cross-coupling reaction
  作者：R.Greg Browning、Hossen Mahmud、Vivek Badarinarayana、Carl J Lovely

  DOI：10.1016/s0040-4039(01)01501-5

  日期：2001.10

  The direct synthesis of non-racemic N-aryl pyrrolidinones through the application of the Buchwald/Hartwig aryl amination reaction is reported. These reactions proceed in generally good yield, with a variety of electron deficient aryl bromides and with retention of stereochemical purity. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
  作者：Elizabeth A. Jurica、Ximao Wu、Kristin N. Williams、Andres S. Hernandez、David S. Nirschl、Richard A. Rampulla、Arvind Mathur、Min Zhou、Gary Cao、Chunshan Xie、Biji Jacob、Hong Cai、Tao Wang、Brian J. Murphy、Heng Liu、Carrie Xu、Lori K. Kunselman、Michael B. Hicks、Qin Sun、Dora M. Schnur、Doree F. Sitkoff、Elizabeth A. Dierks、Atsu Apedo、Douglas B. Moore、Kimberly A. Foster、Mary Ellen Cvijic、Reshma Panemangalore、Neil A. Flynn、Brad D. Maxwell、Yang Hong、Yuan Tian、Jason J. Wilkes、Bradley A. Zinker、Jean M. Whaley、Joel C. Barrish、Jeffrey A. Robl、William R. Ewing、Bruce A. Ellsworth

  DOI：10.1021/acs.jmedchem.6b01559

  日期：2017.2.23

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.