Boc-(S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid | 690254-51-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: Boc-(S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid
• 英文别名: (S)-2-(tert-butyloxycarbonyl)amino-1,2,3,4-tetrahydro-6-(diethylphosphono)-2-naphthalenecarboxylic acid；(2S)-6-diethoxyphosphoryl-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3,4-dihydro-1H-naphthalene-2-carboxylic acid
• CAS: 690254-51-4
• 化学式: C₂₀H₃₀NO₇P
• 分子量: 427.434
• InChiKey: CJGWWRVRTKPYQU-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Boc-(S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid 在 苯甲醚 、 fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-[(S)-2-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-6-(diethoxy-phosphoryl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-oxalamic acid tert-butyl ester
  参考文献：
  名称：

  Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

  摘要：

  Syntheses of N-Boc (S)-4-(diethylphosphono)-(alpha-methyl)phenylalanine [Boc-(alpha-Me)Phe(4-PO3Et2)-OH] (9) and N-Boc (S)-2amino-6-(diethylphosphono)tetralin-2-carboxylic acid [Boc-Atc(6-PO3Et2)-OH] (18) are reported as conformationally-constrained phosphotyrosyl mimetics suitably protected for peptide synthesis. Both syntheses proceeded through chiral arylhalides that are converted to arylphosphonates by palladium-catalyzed cross coupling with diethylphosphite. These amino acid analogues may be useful in the study of cellular signal transduction processes. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.02.005
• 作为产物：
  描述：

  6-溴-2-四氢萘酮 在 palladium on activated charcoal barium dihydroxide 、 lithium hydroxide 、 四(三苯基膦)钯 、 氯化亚砜 、 (S)-(+)-扁桃酸 、 氢气 、 碳酸氢铵 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 112.0h， 生成 Boc-(S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid
  参考文献：
  名称：

  Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

  摘要：

  Syntheses of N-Boc (S)-4-(diethylphosphono)-(alpha-methyl)phenylalanine [Boc-(alpha-Me)Phe(4-PO3Et2)-OH] (9) and N-Boc (S)-2amino-6-(diethylphosphono)tetralin-2-carboxylic acid [Boc-Atc(6-PO3Et2)-OH] (18) are reported as conformationally-constrained phosphotyrosyl mimetics suitably protected for peptide synthesis. Both syntheses proceeded through chiral arylhalides that are converted to arylphosphonates by palladium-catalyzed cross coupling with diethylphosphite. These amino acid analogues may be useful in the study of cellular signal transduction processes. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.02.005

文献信息

• Design and Synthesis of Conformationally Constrained Grb2 SH2 Domain Binding Peptides Employing α-Methylphenylalanyl Based Phosphotyrosyl Mimetics
  作者：Shinya Oishi、Rajeshri G. Karki、Sang-Uk Kang、Xiangzhu Wang、Karen M. Worthy、Lakshman K. Bindu、Marc C. Nicklaus、Robert J. Fisher、Terrence R. Burke

  DOI：10.1021/jm0492709

  日期：2005.2.1

  Previous work has shown that incorporation of either I-aminocyclohexanecarboxylic acid (Ac(6)c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonotetralin-2-carboxylic acid (Atc(6-(POH2)-H-3)) simultaneously presents structural features of both (a-Me)Ppp and Ac(6)c residues. The current study compares the affinity of this tetralin hybrid Atc(6-PO3H2) versus Ac(6)c and (alpha-Me)Ppp residues when incorporated into the pY + I position of a high-affinity Grb2 SH2 domain binding tripeptide platform. The highest binding affinity (K-D = 14.8 nM) was exhibited by the (alpha-Me)Ppp-containing parent, with the corresponding Ac(6)c-containing peptide being nearly 2-fold less potent (K-D = 23.8 nM). The lower KD value was attributable primarily to a 50% increase in off-rate. Replacement of the Ac(6)c residue with the tetralin-based hybrid resulted in a further 4-fold decrease in binding affnity (K-D = 97.8 nM), which was the result of a further 6-fold increase in off-rate, offset by an approximate 45% increase in on-rate. Therefore, by incorporation of the key structural components found in (alpha-Me)Ppp into the Ac(6)c residue, the tetralin hybrid does enhance binding on-rate. However, net binding affinity is decreased due to an associated increase in binding off-rate. Alternatively, global conformational constraint of an ((alpha-Me)Ppp-containing peptide by beta-macrocyclization did result in pronounced elevation of binding affinity, which was achieved primarily through a decrease in the binding off-rate. Mathematical fitting using a simple model that assumed a single binding site yielded an effective KD of 2.28 nM. However this did not closely approximate the data obtained. Rather, use of a complex model that assumed two binding sites resulted in a very close fit of data and provided KD values of 97 pM and 72 nM for the separate sites, respectively. Therefore, although local conformational constraint in the pY + 1 residue proved to be deleterious, global conformational constraint through beta-macrocyclization achieved higher affinity. Similar beta-macrocyclization may potentially be extended to SH2 domain systems other than Grb2, where bend geometries are required.