N-(L-alanyl)-L-phenylglycine tert-butyl ester | 327052-53-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(L-alanyl)-L-phenylglycine tert-butyl ester
• 英文别名: N-(L-alanyl)-(2S)-2-phenylglycine tert-butyl ester；H-L-Ala-L-Phg-O^tBu；N-(l-alanyl)-(2s)-2-phenylglycine tert-butyl ester；tert-butyl (2S)-2-[[(2S)-2-aminopropanoyl]amino]-2-phenylacetate
• CAS: 327052-53-9
• 化学式: C₁₅H₂₂N₂O₃
• 分子量: 278.351
• InChiKey: KKMUHPHLSBRKNM-JQWIXIFHSA-N

物化性质

• 沸点：
  431.1±40.0 °C(Predicted)
• 密度：
  1.104±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(L-alanyl)-L-phenylglycine tert-butyl ester 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 N-[N-(tert-butyloxycarbonyl)-L-alanyl]-(2S)-2-phenylglycine
  参考文献：
  名称：

  Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

  摘要：

  我们报告了以 3,5-二氟甲酰基丙氨酰或 3,5-二氟苯乙酰基丙氨酰为骨架、与各种杂环或肽基偶联的两个系列化合物的合成。我们评估了这两个系列的化合物对阿尔茨海默病（AD）病理靶酶 β-分泌酶（BACE-1）的抑制特性。我们发现，从带有曼地尔分子的香豆素衍生物的外消旋混合物 7 中得到的两种非对映异构体都是本研究中最有效的 BACE-1 抑制剂（IC50 = 1 × 10-6 M）。对所得结果进行分析后得出的假设是，引入二氟曼丁酰残基取代二氟苯乙酰基可能会诱导β-分泌酶抑制活性。

  DOI：

  10.1071/ch05102
• 作为产物：
  描述：

  L-苯甘氨酸 在 palladium on activated charcoal 高氯酸 、 氢气 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 N-(L-alanyl)-L-phenylglycine tert-butyl ester
  参考文献：
  名称：

  Parallel synthesis of DAPT derivatives and their γ-secretase-inhibitory activity

  摘要：

  Parallel synthesis of the C-terminal-modified DAPT (1) derivatives was accomplished utilizing our novel resin 7. Condensation reaction of the N-acylamino acid 10 with the amines 11a-o proceeded smoothly to give the corresponding amides 6a-o without any epimerization. Among the analogues, the benzophenonemethyl amide derivative 6o showed 30 times more potent activity than the original DAPT (1). (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.01.067

文献信息

• A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives
  作者：Ciby J. Abraham、Daniel H. Paull、Tefsit Bekele、Michael T. Scerba、Travis Dudding、Thomas Lectka

  DOI：10.1021/ja806818a

  日期：2008.12.17

  enantioenriched, alpha-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph(3)P)(2)PdCl(2) was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations

  我们报告了一种不寻常的双功能连续杂狄尔斯-阿尔德/开环反应的详细合成和机理研究，其中手性金属络合乙烯酮烯醇化物与邻醌反应，以优异的产率提供高度对映体富集的α-羟基化羰基衍生物。与金鸡纳生物碱衍生物一起筛选了许多路易斯酸；令人惊讶的是，发现反式-(Ph(3)P)(2)PdCl(2)可显着提高产率和反应速率。通过分子建模以及红外、紫外和核磁共振光谱探索了一系列路易斯酸结合基序。我们的观察记录了一个基本的机制“转换”，即串联路易斯碱/路易斯酸活化的金属烯醇化物的形成，优先于金属配位的醌物种（如在邻醌衍生物的其他反应中观察到的）。这种新方法被应用于多种药物靶标的合成，每种药物靶标均具有高产率和对映选择性。
• Peptide Bond Formation of Amino Acids by Transient Masking with Silylating Reagents
  作者：Wataru Muramatsu、Hisashi Yamamoto

  DOI：10.1021/jacs.1c02600

  日期：2021.5.12

  A one-pot peptide bond-forming reaction has been developed using unprotected amino acids and peptides. Two different silylating reagents, HSi[OCH(CF3)2]3 and MTBSTFA, are instrumental for the successful implementation of this approach, being used for the activation and transient masking of unprotected amino acids and peptides at C-termini and N-termini, respectively. Furthermore, CsF and imidazole

  使用未受保护的氨基酸和肽开发了一种一锅式肽键形成反应。两种不同的甲硅烷基化试剂 HSi[OCH(CF 3 ) 2 ] 3和 MTBSTFA 有助于成功实施该方法，用于激活和瞬时掩蔽C端和N端未受保护的氨基酸和肽， 分别。此外，CsF 和咪唑用作催化剂，活化 HSi[OCH(CF 3 ) 2 ] 3并且还加速化学选择性硅烷化。这种方法是通用的，因为它可以容忍带有一系列官能团的侧链，同时提供高达 99% 以上的相应肽收率，而无需任何外消旋或聚合。
• Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy
  作者：Gilles Quéléver、Philippe Kachidian、Christophe Melon、Cédrik Garino、Younes Laras、Nicolas Pietrancosta、Mahmoud Sheha、Jean Louis Kraus

  DOI：10.1039/b504988a

  日期：——

  Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Aβ peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a γ-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Aβ peptide production measurements by specific in vitro assays (γ-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent γ-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug 2 will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this γ-secretase inhibitor on the immune cells could be reduced.

  δ-分泌酶是负责裂解淀粉样前体蛋白（APP）产生致病性δ肽的酶之一，抑制δ-分泌酶是治疗阿尔茨海默病的一种有吸引力的方法。我们设计了一种带有抗坏血酸分子的δ-分泌酶抑制剂，可以将药物特异性地输送到大脑。一方面，通过特定的体外试验（无δ-分泌酶细胞试验和基于 HEK 293 APP 转染细胞的细胞试验）测量了δ肽的生成量，另一方面，通过对动物模型进行药代动力学研究，新抑制剂显示出良好的药代动力学特征以及强大的体外δ-分泌酶抑制活性。根据研究结果，预计药物 2 将主要进入中枢神经系统，在外周组织的扩散量较低。因此，这种δ-分泌酶抑制剂对免疫细胞的副作用可以减少。
• Parallel synthesis of DAPT derivatives and their γ-secretase-inhibitory activity
  作者：Toshiyuki Kan、Yusuke Tominari、Kentaro Rikimaru、Yuichi Morohashi、Hideaki Natsugari、Taisuke Tomita、Takeshi Iwatsubo、Tohru Fukuyama

  DOI：10.1016/j.bmcl.2004.01.067

  日期：2004.4

  Parallel synthesis of the C-terminal-modified DAPT (1) derivatives was accomplished utilizing our novel resin 7. Condensation reaction of the N-acylamino acid 10 with the amines 11a-o proceeded smoothly to give the corresponding amides 6a-o without any epimerization. Among the analogues, the benzophenonemethyl amide derivative 6o showed 30 times more potent activity than the original DAPT (1). (C) 2004 Elsevier Ltd. All rights reserved.
• Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues
  作者：Nicolas Pietrancosta、Gilles Quéléver、Younes Laras、Cédrik Garino、Stéphane Burlet、Jean Louis Kraus

  DOI：10.1071/ch05102

  日期：——

  We report the synthesis of two series of compounds with 3,5-difluoromandelyl-alanyl or 3,5-difluorophenylacetyl-alanyl backbones coupled to various heterocyclic or peptidic moieties. These two series of compounds were evaluated for their inhibitory properties on β-secretase (BACE-1) enzymatic assay, a target enzyme for Alzheimer’s disease (AD) pathology. We found that both diastereomers obtained from the racemic mixture 7 of the coumarin derivative bearing a mandelyl moiety were the most potent BACE-1 inhibitors studied in this work (IC50 = 1 × 10−6 M). Analysis of the obtained results led to the hypothesis that introduction of a difluoromandelyl residue in place of a difluorophenylacetyl moiety may induce β-secretase inhibitory activity.

  我们报告了以 3,5-二氟甲酰基丙氨酰或 3,5-二氟苯乙酰基丙氨酰为骨架、与各种杂环或肽基偶联的两个系列化合物的合成。我们评估了这两个系列的化合物对阿尔茨海默病（AD）病理靶酶 β-分泌酶（BACE-1）的抑制特性。我们发现，从带有曼地尔分子的香豆素衍生物的外消旋混合物 7 中得到的两种非对映异构体都是本研究中最有效的 BACE-1 抑制剂（IC50 = 1 × 10-6 M）。对所得结果进行分析后得出的假设是，引入二氟曼丁酰残基取代二氟苯乙酰基可能会诱导β-分泌酶抑制活性。