(2RS)-2-benzyl-1-benzyloxycarbonyl-2-carboxylazetidine | 849919-57-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2RS)-2-benzyl-1-benzyloxycarbonyl-2-carboxylazetidine
• 英文别名: 1-Cbz-2-benzyl-2-azetidinecarboxylic acid；2-benzyl-1-phenylmethoxycarbonylazetidine-2-carboxylic acid
• CAS: 849919-57-9
• 化学式: C₁₉H₁₉NO₄
• 分子量: 325.364
• InChiKey: NBXHGMSWYSWAHL-UHFFFAOYSA-N

物化性质

• 沸点：
  509.9±50.0 °C(Predicted)
• 密度：
  1.304±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2RS)-2-benzyl-1-benzyloxycarbonyl-2-carboxylazetidine 在 TEA 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2S)-2-[(2-benzyl-1-phenylmethoxycarbonylazetidine-2-carbonyl)amino]propanoic acid
  参考文献：
  名称：

  From 1-Acyl-β-lactam Human Cytomegalovirus Protease Inhibitors to 1-Benzyloxycarbonylazetidines with Improved Antiviral Activity. A Straightforward Approach To Convert Covalent to Noncovalent Inhibitors

  摘要：

  Starting from the structure of known beta-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/ Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10-50 mu M, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the beta-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.

  DOI：

  10.1021/jm0492812
• 作为产物：
  描述：

  (2RS)-2-benzyl-1-benzyloxycarbonyl-2-metoxycarbonylazetidine 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 以92%的产率得到(2RS)-2-benzyl-1-benzyloxycarbonyl-2-carboxylazetidine
  参考文献：
  名称：

  From 1-Acyl-β-lactam Human Cytomegalovirus Protease Inhibitors to 1-Benzyloxycarbonylazetidines with Improved Antiviral Activity. A Straightforward Approach To Convert Covalent to Noncovalent Inhibitors

  摘要：

  Starting from the structure of known beta-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/ Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10-50 mu M, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the beta-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.

  DOI：

  10.1021/jm0492812

文献信息

• Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors
  作者：Paula Pérez-Faginas、M. Teresa Aranda、M. Teresa García-López、Robert Snoeck、Graciela Andrei、Jan Balzarini、Rosario González-Muñiz

  DOI：10.1016/j.bmc.2010.12.052

  日期：2011.2

  SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by H-1 NMR as a gamma-type reverse turn, seems to have influence on the activity of these molecules. (C) 2010 Elsevier Ltd. All rights reserved.
• Azetidine-Derived Amino Acids versus Proline Derivatives. Alternative Trends in Reverse Turn Induction
  作者：José Luis Baeza、Guillermo Gerona-Navarro、Jesús Pérez de Vega、M. Teresa García-López、Rosario González-Muñiz、Mercedes Martín-Martínez

  DOI：10.1021/jo701746w

  日期：2008.3.1

  [Graphics]The influence of 2-alkyl-2-carboxyazetidines (Aze) on the 3D structure of model tetrapeptides (RCO)-C-2-2-R(1)Aze-L-Ala-NHMe has been analyzed by molecular modeling, H-1 NMR, and FT-IR studies. The conformational constraints introduced by the four-membered ring resulted in an effective way to stabilize gamma-turn-like conformations in these short peptides. The conformational preferences of these Aze-containing peptides have been compared to those of the corresponding peptide analogues containing Pro or a-MePro in the place of 2-alkyl-Aze residue. In the model studied, both Pro and Aze derivatives are able to induce reverse turns, but the nature of the turn is different as a function of the ring size. While the five-membered ring of Pro tends to induce beta-turns, as previously suggested by different authors, the four-membered ring of Aze residues forces the peptide to preferentially adopt gamma-turn conformations. In both cases, the presence of an alkyl group at the alpha-position of Pro or the azetidine-2-carboxylate ring enhances significantly the turn-inducing ability. These results might open the opportunity of using 2-alkyl-Aze residues as versatile tools in defining the role of gamma-turn structures within the bioactive conformation of selected peptides, and represent an alternative to Pro derivatives as turn inducers.
• 2-Alkyl-2-carboxy-azetidines as scaffolds for the induction of γ-turns
  作者：José Luis Baeza、Guillermo Gerona-Navarro、Ma Jesús Pérez de Vega、Ma Teresa García-López、Rosario González-Muñiz、Mercedes Martín-Martínez

  DOI：10.1016/j.tetlet.2007.03.126

  日期：2007.5

  To investigate the ability of 2-alkyl-2-carboxy-azetidines (Azx) to induce reverse turns when incorporated into peptides, RCO-Azx-L-A1a-NHMe dipeptide derivatives were selected as simplified tetrapeptide models, in which the azetidine residue is incorporated at the i + 1 position. Molecular modelling, H-1 NMR and FTIR studies showed the high tendency of the model tetrapeptides to adopt gamma-turn conformations, indicating that these azetidine-containing amino acids could serve as general gamma-turn promoters. (c) 2007 Elsevier Ltd. All rights reserved.
• From 1-Acyl-β-lactam Human Cytomegalovirus Protease Inhibitors to 1-Benzyloxycarbonylazetidines with Improved Antiviral Activity. A Straightforward Approach To Convert Covalent to Noncovalent Inhibitors
  作者：Guillermo Gerona-Navarro、M. Jesús Pérez de Vega、M. Teresa García-López、Graciela Andrei、Robert Snoeck、Erik De Clercq、Jan Balzarini、Rosario González-Muñiz

  DOI：10.1021/jm0492812

  日期：2005.4.1

  Starting from the structure of known beta-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/ Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10-50 mu M, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the beta-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.