diethyl (S_S,R)-N-(p-bromobenzenesulfinyl)-2-amino-2-methylpropylphosphonate | 873586-59-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diethyl (S_S,R)-N-(p-bromobenzenesulfinyl)-2-amino-2-methylpropylphosphonate
• 英文别名: (S)-4-bromo-N-[(1R)-1-diethoxyphosphoryl-2-methylpropyl]benzenesulfinamide
• CAS: 873586-59-5
• 化学式: C₁₄H₂₃BrNO₄PS
• 分子量: 412.285
• InChiKey: ZMFXYAZGFPAKSP-PEBXRYMYSA-N

物化性质

• 沸点：
  492.1±55.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  83.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  diethyl (S_S,R)-N-(p-bromobenzenesulfinyl)-2-amino-2-methylpropylphosphonate 在 四(三苯基膦)钯 sodium carbonate 、 间氯过氧苯甲酸 作用下， 以 水 、 甲苯 为溶剂， 生成 diethyl (R)-[1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate
  参考文献：
  名称：

  α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs

  摘要：

  (R)-alpha-Biphenyisulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, alpha-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-p-bromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-alpha-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1, -2, -3, -7, -8, -9, -13 and -14 showed IC50 in the range of nM in most cases. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.10.047
• 作为产物：
  描述：

  (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-4-bromobenzenesulfinate 在 titanium(IV) tetraethanolate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 6.33h， 生成 diethyl (S_S,R)-N-(p-bromobenzenesulfinyl)-2-amino-2-methylpropylphosphonate
  参考文献：
  名称：

  Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates

  摘要：

  Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.

  DOI：

  10.1021/jm050787+

文献信息

• α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs
  作者：Alessandro Biasone、Paolo Tortorella、Cristina Campestre、Mariangela Agamennone、Serena Preziuso、Marika Chiappini、Elisa Nuti、Paolo Carelli、Armando Rossello、Fernando Mazza、Carlo Gallina

  DOI：10.1016/j.bmc.2006.10.047

  日期：2007.1

  (R)-alpha-Biphenyisulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, alpha-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-p-bromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-alpha-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1, -2, -3, -7, -8, -9, -13 and -14 showed IC50 in the range of nM in most cases. (c) 2006 Elsevier Ltd. All rights reserved.
• Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates
  作者：Giorgio Pochetti、Enrico Gavuzzo、Cristina Campestre、Mariangela Agamennone、Paolo Tortorella、Valerio Consalvi、Carlo Gallina、Oliver Hiller、Harald Tschesche、Paul A. Tucker、Fernando Mazza

  DOI：10.1021/jm050787+

  日期：2006.2.1

  Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.