methyl N-(benzyloxycarbonyl)aminomethylphosphonochloridate | 80556-22-5

• 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: methyl N-(benzyloxycarbonyl)aminomethylphosphonochloridate
• 英文别名: benzyl N-[[chloro(methoxy)phosphoryl]methyl]carbamate
• CAS: 80556-22-5
• 化学式: C₁₀H₁₃ClNO₄P
• 分子量: 277.644
• InChiKey: RZOYTECSSCDOQZ-UHFFFAOYSA-N

物化性质

• 密度：
  1.325±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl N-(benzyloxycarbonyl)aminomethylphosphonochloridate 在 lithium hydroxide 、 4 A molecular sieve 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 72.0h， 生成 (2S)-2-[(2S)-2-[[hydroxy(phenylmethoxycarbonylaminomethyl)phosphoryl]amino]-4-methylpentanoyl]oxy-4-methylpentanoic acid
  参考文献：
  名称：

  Differential binding energy: a detailed evaluation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorus-containing inhibitors

  摘要：

  Two series of phosphorus-containing peptide analogues, 3 (Cbz-Gly-psi(PO2-CH2)Leu-Xaa) and 4 (Cbz-Gly-psi-(PO2-NH)Leu-psi[CO2]Xaa), have been synthesized and evaluated as inhibitors of the zinc endopeptidase thermolysin. In comparison with the previously reported phosphonamidates 1, the phosphinates 3 lose only 0.1 kcal/mol in binding affinity, whereas the depsipeptides 4 are bound 2.7 kcal/mol more weakly; these values are contrasted to the 4.0 kcal/mol reduction in binding affinity observed for the phosphonates 2 (Cbz-Gly-psi(PO2-O)Leu-Xaa) in comparison to 1 (Cbz-Gly-psi(PO2-NH)Leu-Xaa). The observed effects are interpreted through consideration of the differences in active-site and solvent interactions. For the comparison between the diamides 1 and the depsipeptides 4, a full accounting of the balance between these interactions can be approached. The arylphosphonates 5 (Aryl-psi(PO2-O)Leu-Leu) were synthesized and evaluated to investigate the importance of phosphonate basicity on the overall binding affinity of these zinc-coordinating inhibitors; the inhibitor K(i) values were found to be independent of phosphonate p(K)a, indicating that the basicity of the phosphonate moiety exerts counterbalancing effects on the energies of zinc coordination and solvation. For analysis of the influence of structural variations on observed affinity, the definition of "differential binding energy" is introduced as a practical alternative to the concept of "intrinsic binding energy".

  DOI：

  10.1021/ja00001a043
• 作为产物：
  描述：

  diphenyl [(([(phenylmethyl)oxy]carbonyl)amino)methyl]phosphonate 在 Alkaline 作用下， 生成 methyl N-(benzyloxycarbonyl)aminomethylphosphonochloridate
  参考文献：
  名称：

  Bartlett, Paul A.; Marlowe, Charles K., Phosphorus and Sulfur and the Related Elements, 1987, vol. 30, p. 537 - 544

  摘要：

  DOI：

文献信息

• Reactive species formed from N-benzyloxycarbonyl α-aminophosphonochloridates and triethylamine: probable identity and implications for synthesisElectronic supplementary information (ESI) available: NMR data for compounds 4 and 5 (X = Cl) and the products formed by them with Et3N. See http://www.rsc.org/suppdata/cc/b1/b109231f/
  作者：Paul M. Cullis、Martin J. P. Harger

  DOI：10.1039/b109231f

  日期：2002.2.27

  The sterically congested phosphonochloridate BnOCONHCMe2P(O)(OMe)Cl reacts rapidly with Et3N to give what is thought to be an oxazaphospholine oxide 7 (and Et3NHCl); unhindered BnOCONHCH2P(O)(OMe)Cl seems to react in the same way, in which case the product is not a phosphonylammonium salt as has been suggested.

  立体拥塞的膦酰氯 BnOCONHCMe2P(O)(OMe)Cl 与 Et3N 快速反应，生成被认为是噁唑磷啉的氧化物 7（和 Et3NHCl）；未受阻的 BnOCONHCH2P(O)(OMe)Cl 似乎也以同样的方式反应，在这种情况下，生成物并不像人们认为的那样是膦酰铵盐。
• Intramolecular nucleophilic catalysis and the exceptional reactivity of N-benzyloxycarbonyl α-aminophosphonochloridates
  作者：Paul M. Cullis、Martin J. P. Harger

  DOI：10.1039/b204935j

  日期：——

  The chloridate BnOCONHCH2P(O)(OMe)Cl is 103–104 times more reactive than ClCH2P(O)(OMe)Cl in substitution with PriOH; the α,α-dimethyl analogue is no less reactive and the N-methyl derivative is more reactive; nucleophilic participation (catalysis) by the carbamate group is implicated.

  氯酸盐 BnOCONHCH2P(O)(OMe)Cl 与 PriOH 发生取代反应的反应活性是 ClCH2P(O)(OMe)Cl 的 103â104 倍；δ,δ-二甲基类似物的反应活性不低，而 N-甲基衍生物的反应活性更高；这说明氨基甲酸酯基团具有亲核参与（催化作用）。
• Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
  作者：Stefan G. Krimmer、Jonathan Cramer、Michael Betz、Veronica Fridh、Robert Karlsson、Andreas Heine、Gerhard Klebe

  DOI：10.1021/acs.jmedchem.6b00998

  日期：2016.12.8

  A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S-2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P-2' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.
• A phosphonamidate dipeptide analog as an inhibitor of carboxypeptidase A
  作者：Neil E. Jacobsen、Paul A. Bartlett

  DOI：10.1021/ja00393a026

  日期：1981.2
• Differential binding energy: a detailed evaluation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorus-containing inhibitors
  作者：Bradley Morgan、John M. Scholtz、Marcus D. Ballinger、Ilan D. Zipkin、Paul A. Bartlett

  DOI：10.1021/ja00001a043

  日期：1991.1

  Two series of phosphorus-containing peptide analogues, 3 (Cbz-Gly-psi(PO2-CH2)Leu-Xaa) and 4 (Cbz-Gly-psi-(PO2-NH)Leu-psi[CO2]Xaa), have been synthesized and evaluated as inhibitors of the zinc endopeptidase thermolysin. In comparison with the previously reported phosphonamidates 1, the phosphinates 3 lose only 0.1 kcal/mol in binding affinity, whereas the depsipeptides 4 are bound 2.7 kcal/mol more weakly; these values are contrasted to the 4.0 kcal/mol reduction in binding affinity observed for the phosphonates 2 (Cbz-Gly-psi(PO2-O)Leu-Xaa) in comparison to 1 (Cbz-Gly-psi(PO2-NH)Leu-Xaa). The observed effects are interpreted through consideration of the differences in active-site and solvent interactions. For the comparison between the diamides 1 and the depsipeptides 4, a full accounting of the balance between these interactions can be approached. The arylphosphonates 5 (Aryl-psi(PO2-O)Leu-Leu) were synthesized and evaluated to investigate the importance of phosphonate basicity on the overall binding affinity of these zinc-coordinating inhibitors; the inhibitor K(i) values were found to be independent of phosphonate p(K)a, indicating that the basicity of the phosphonate moiety exerts counterbalancing effects on the energies of zinc coordination and solvation. For analysis of the influence of structural variations on observed affinity, the definition of "differential binding energy" is introduced as a practical alternative to the concept of "intrinsic binding energy".