tert-butyl 2-[methyl-[(2S)-pyrrolidine-2-carbonyl]amino]acetate | 63219-23-8

• 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: tert-butyl 2-[methyl-[(2S)-pyrrolidine-2-carbonyl]amino]acetate
• CAS: 63219-23-8
• 化学式: C₁₂H₂₂N₂O₃
• 分子量: 242.318
• InChiKey: KEMVVMOWWJSGCD-VIFPVBQESA-N

物化性质

• 沸点：
  360.8±42.0 °C(Predicted)
• 密度：
  1.073±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-[methyl-[(2S)-pyrrolidine-2-carbonyl]amino]acetate 在 palladium on activated charcoal 4-二甲氨基吡啶 、 N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride 、 氢气 、 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， -10.0~25.0 ℃ 、101.33 kPa 条件下， 反应 145.0h， 生成 (3-(benzyloxy)-4-methyl-2-nitrobenzoyl)-L-threonyl-D-valyl-L-prolyl-sarcosyl-N-methyl-L-valine lactone
  参考文献：
  名称：

  Toward the Design of an RNA:DNA Hybrid Binding Agent

  摘要：

  One characteristic function of the retroviruses, which is generally not found in normal eukaryotic cells, is production of a long RNA:DNA hybrid in the viral replication phase. If agents are designed which bind only to the RNA:DNA hybrid, but neither to DNA nor to RNA, such agents will be able to inhibit specifically the RNase H activity of retroviral reverse transcriptase, and therefore will suppress viral replication. Actinomycin D binds to double-stranded DNA, but not to RNA, because steric hindrance between the 2-amino group of the phenoxazinone ring and the 2'-hydroxyl group of RNA prevents intercalation of the antibiotic. However, if the C8-H in the phenoxazinone ring is replaced by an aromatic nitrogen N8, a strong hydrogen bond acceptor, this analog (N8-actinomycin D) might be able to bind intercalatively to an RNA:DNA hybrid by forming an additional hydrogen bond between N8 and the 2'-hydroxyl group of guanosine ribose. This hypothesis has been tested by a molecular mechanics calculation using a model structure of the complex between N8-actinomycin D and a small RNA:DNA hybrid, r(GC):d(GC). The results of the molecular mechanics calculation suggest that N8-actinomycin D can intercalatively bind to the RNA: DNA hybrid by making an additional intracomplex hydrogen bond. This hydrogen bonding capability of N8 has been confirmed in the crystal structure of the chromophore of N8-actinomycin D. Thus, N8-actinomycin D has been synthesized by coupling the pyridine and benzene fragments obtained independently. A binding study indicates that both actinomycin D and N8-actinomycin D bind intercalatively not only to DNA:DNA double strands but also to RNA:DNA hybrids. Although the overall binding capacity of N8-actinomycin D is reduced substantially in comparison with that of actinomycin D itself, N8-actinomycin D tends to bind relatively more favorably than actinomycin D to the RNA:DNA hybrids. Thus, this initial attempt at designing an RNA:DNA hybrid binding agent appears to be successful. However, it is necessary to modify the agent further to increase its RNA:DNA hybrid binding character and to decrease the DNA:DNA binding character, in order to make a useful RNA:DNA hybrid binding agent.

  DOI：

  10.1021/ja00085a002
• 作为产物：
  描述：

  (benzyloxycarbonyl)sarcosine tert-butyl ester 在 palladium on activated charcoal 氢气 、 二乙胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 1.5h， 生成 tert-butyl 2-[methyl-[(2S)-pyrrolidine-2-carbonyl]amino]acetate
  参考文献：
  名称：

  使用新型1 H-苯并咪唑鎓盐高效合成含有N-甲基化氨基酸残基的位阻受阻肽

  摘要：

  设计，合成了新型1 H-苯并咪唑型肽偶联剂CMBI，证明其在促进空间位阻酰胺和酯键形成方面是有效的。通过模型反应试验和成功合成了各种受阻寡肽和含有N-甲基氨基酸残基的肽段，证明了其高效率，其反应速度快，外消旋化程度低且产率高。提出了由试剂介导的酰胺键形成机理。

  DOI：

  10.1016/s0040-4020(00)00963-7

文献信息

• Synthesis and properties of some peptide analogs of actinomycin D
  作者：Anthony B. Mauger、Oswald A. Stuart、Edward Katz

  DOI：10.1021/jm00108a009

  日期：1991.4

  Analogues of actinomycin D (AMD) were synthesized in which amino acid replacements were made at various sites in the peptide moieties. These include (i) replacement of both N-methylvalines by N-methylleucine, (ii) replacement of both sarcosines by N-[2-(methoxycarbonyl)ethyl]glycine, and (iii) replacement of one or both D-valines by D-threonine. The purpose of replacements ii and iii was to ascertain

  合成了放线菌素D（AMD）的类似物，其中在肽部分的不同位点进行了氨基酸置换。这些包括（i）用N-甲基亮氨酸替换两个N-甲基缬氨酸，（ii）用N- [2-（甲氧基羰基乙基）甘氨酸替换两个肌氨酸，和（iii）用D替换一个或两个D-缬氨酸。 -苏氨酸。替代ii和iii的目的是确定引入新的侧链对生物学活性的影响，该侧链可以进行功能化以允许连接载体分子（例如抗体）。NMR数据表明没有类似物具有与AMD显着不同的溶液构象。与DNA的差异光谱表明，置换i增强了结合，而其他类似物与DNA的结合则不那么牢固。所有类似物的抗菌活性均低于AMD。相反，5,5'-（MeLeu）2AMD在低约100倍的浓度下显示出与AMD相当的体外抗肿瘤活性。
• Role of D-Valine Residues in the Antitumor Drug Actinomycin D:Replacement of D-Valines with Other D-Amino Acids Changes the DNA Binding Characteristics and Transcription Inhibitory Activities
  作者：Wenhua Chu、Miho Shinomiya、Kazuyo Y. Kamitori、Shigehiro Kamitori、Robert G. Carlson、Robert F. Weaver、Fusao Takusagawa

  DOI：10.1021/ja00097a003

  日期：1994.9

  D-valine analogues of the antitumor drug actinomycin D, in which D-valine residues were replaced with D-threonine, D-tyrosine, D-phenylalanine, and D-O-methyltyrosine residues, have been totally synthesized. The crystal structure of the D-O-methyltyrosine analogue has been determined (a = b = 21.352(6), c = 44.525(9) Angstrom space group P4(1)2(1)2; R = 0.19 for 803 out of 1114 reflections at 1.8 Angstrom resolution data). Replacements of D-valines did not change the overall conformation of the molecule, and the substituted groups were located on the side opposite to the DNA binding site, suggesting that the analogues can bind intercalatively at 5'-GC-3' sequences of DNA like actinomycin D does. In the crystals, the analogue molecules constitute a tight dimer, and a pair of stacked chromophores of the dimer was further sandwiched by two methoxyphenyl groups of neighboring molecules. These strong aromatic-aromatic stacking forces among the molecules appear to reduce very much the water solubility of the aromatic analogues. The characteristics of binding of the analogues to various DNA's including d(GAAGCTTC)(2), d(GTTGCAAC)(2), poly(dA-dT), poly(dG-dC), and calf thymus DNA have been examined by using the visible spectrum methods. Difference spectra of actinomycin D and the analogues with oligonucleotides indicated that the analogues bind intercalatively to the DNA, as actinomycin D does, but the association constants were reduced to approximately one-half that of actinomycin D. The spectra of the aromatic analogues titrated with calf thymus DNA indicated that the aromatic analogues bound somehow differently to the longer DNA's. A simple profile analysis of the spectra suggested that the aromatic analogues bound to calf thymus DNA not only with intercalation, as actinomycin D does, but also with side binding. Nevertheless, the association constants of the aromatic analogues to calf thymus DNA with the intercalation mode were found to be quite similar to those of the short oligonucleotides. This conclusion has been supported by the melting behaviors of the DNA with the aromatic analogues, in which the melting curves of the analogues were superimposable on the melting curve of DNA with actinomycin D, suggesting that the aromatic analogue molecules were intercalated into the DNA. The inhibitory activities of actinomycin D and analogues on RNA polymerase in vitro were examined using calf thymus DNA and E. coli RNA polymerase. All actinomycin D analogues severely inhibited RNA synthesis at relatively low drug concentrations. In general, inhibitory activities of the analogues on the RNA synthesis were found to be correlated with those of DNA binding characteristics. However, the analogue in which D-phenylalanine replaced D-valines inhibited RNA synthesis more strongly than actinomycin D itself, but this-analogue bound to the DNA's much more weakly than actinomycin D. In this study, the D-valine residues in the cyclic depsipeptides of actinomycin D were found not to be directly involved in DNA binding, but this amino acid residue was found to be an important biological modulator of the antibiotic. Although the D-valine is a hydrophobic amino acid residue, this amino acid residue appears to play an important role in increasing the water solubility of the antibiotic. Replacements of D-valine residues reduced drastically the water solubility of the analogues, and consequently; this physical character of the analogues reduced their capacities for binding to DNA. As a result, the biological activities of the analogues were generally decreased.
• Toward the Design of an RNA:DNA Hybrid Binding Agent
  作者：Wenhua Chu、Shigehiro Kamitori、Miho Shinomiya、Robert G. Carlson、Fusao Takusagawa

  DOI：10.1021/ja00085a002

  日期：1994.3

  One characteristic function of the retroviruses, which is generally not found in normal eukaryotic cells, is production of a long RNA:DNA hybrid in the viral replication phase. If agents are designed which bind only to the RNA:DNA hybrid, but neither to DNA nor to RNA, such agents will be able to inhibit specifically the RNase H activity of retroviral reverse transcriptase, and therefore will suppress viral replication. Actinomycin D binds to double-stranded DNA, but not to RNA, because steric hindrance between the 2-amino group of the phenoxazinone ring and the 2'-hydroxyl group of RNA prevents intercalation of the antibiotic. However, if the C8-H in the phenoxazinone ring is replaced by an aromatic nitrogen N8, a strong hydrogen bond acceptor, this analog (N8-actinomycin D) might be able to bind intercalatively to an RNA:DNA hybrid by forming an additional hydrogen bond between N8 and the 2'-hydroxyl group of guanosine ribose. This hypothesis has been tested by a molecular mechanics calculation using a model structure of the complex between N8-actinomycin D and a small RNA:DNA hybrid, r(GC):d(GC). The results of the molecular mechanics calculation suggest that N8-actinomycin D can intercalatively bind to the RNA: DNA hybrid by making an additional intracomplex hydrogen bond. This hydrogen bonding capability of N8 has been confirmed in the crystal structure of the chromophore of N8-actinomycin D. Thus, N8-actinomycin D has been synthesized by coupling the pyridine and benzene fragments obtained independently. A binding study indicates that both actinomycin D and N8-actinomycin D bind intercalatively not only to DNA:DNA double strands but also to RNA:DNA hybrids. Although the overall binding capacity of N8-actinomycin D is reduced substantially in comparison with that of actinomycin D itself, N8-actinomycin D tends to bind relatively more favorably than actinomycin D to the RNA:DNA hybrids. Thus, this initial attempt at designing an RNA:DNA hybrid binding agent appears to be successful. However, it is necessary to modify the agent further to increase its RNA:DNA hybrid binding character and to decrease the DNA:DNA binding character, in order to make a useful RNA:DNA hybrid binding agent.
• Highly Efficient Synthesis of Sterically Hindered Peptides Containing N-Methylated Amino Acid Residues using a Novel 1H-Benzimidazolium Salt
  作者：Peng Li、Jie Cheng Xu

  DOI：10.1016/s0040-4020(00)00963-7

  日期：2000.12

  Novel 1H-benzimidazolium type peptide coupling reagent, CMBI, was designed, synthesized, and shown to be efficient in the promotion of the formation of sterically hindered amide and ester bonds. Its high efficiency was proved by model reaction tests and the successful synthesis of various hindered oligopeptides and peptide segments containing N-methyl amino acid residues with fast reaction speeds, low

  设计，合成了新型1 H-苯并咪唑型肽偶联剂CMBI，证明其在促进空间位阻酰胺和酯键形成方面是有效的。通过模型反应试验和成功合成了各种受阻寡肽和含有N-甲基氨基酸残基的肽段，证明了其高效率，其反应速度快，外消旋化程度低且产率高。提出了由试剂介导的酰胺键形成机理。