D-N-BOC-4-fluoro-3-nitrophenylalanine | 173775-54-7

• 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: D-N-BOC-4-fluoro-3-nitrophenylalanine
• 英文别名: (R)-N-(tert-butoxycarbonyl)-4-fluoro-3-nitrophenylalanine；D-Phenylalanine, N-[(1,1-dimethylethoxy)carbonyl]-4-fluoro-3-nitro-；(2R)-3-(4-fluoro-3-nitrophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 173775-54-7
• 化学式: C₁₄H₁₇FN₂O₆
• 分子量: 328.297
• InChiKey: JKJBFOWSXXVZCU-SNVBAGLBSA-N

物化性质

• 沸点：
  518.8±50.0 °C(Predicted)
• 密度：
  1.341±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  D-N-BOC-4-fluoro-3-nitrophenylalanine 在 3 A molecular sieve 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 2.5h， 生成 (9S,12R)-12-[N-(tert-butyloxycarbonyl)amino]-2,11-dioxo-4-hydroxy-9-methoxycarbonyl-16-nitro-10-azatricyclo[12.2.2.13,7]nonadeca-3,5,7(19),14,16,17-hexaene
  参考文献：
  名称：

  Total Synthesis of an Antitumor Agent RA-VII via an Efficient Preparation of Cycloisodityrosine

  摘要：

  Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RA-VII(1) were described. An intramolecular SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L(3-hydroxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)-L-(3,4-dihydroxyphenlalanyl)]-L-4-fluoro-3- nitrophenylalaninate ((9S,12S)-11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).

  DOI：

  10.1021/jo990432w
• 作为产物：
  描述：

  4-氟-3-硝基苄醇 在 盐酸 、 sodium hydroxide 、 氯化亚砜 、 N-benzylcinchoninium bromide 、 三溴化磷 、 碳酸氢钠 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 水 为溶剂， 生成 D-N-BOC-4-fluoro-3-nitrophenylalanine
  参考文献：
  名称：

  糖肽抗生素的合成研究：替考拉宁的16元环三肽（DOEG环）系统的合成

  摘要：

  替考拉宁的16元环状多益环体系，其形成用于终端的羧酸区的结合口袋的合成d -Ala- d经由线性三肽的macroetherification细菌细胞壁的-Ala 20进行说明。

  DOI：

  10.1016/0040-4039(96)00459-5

文献信息

• Synthesis of a model bicyclic C-O-D-O-E ring of vancomycin by a one-pot, double SNAr based macrocyclization
  作者：Ren� Beugelmans、Mich�le Bois-Choussy、Caroline Vergne、Jean-Philippe Bouillon、Jieping Zhu

  DOI：10.1039/cc9960001029

  日期：——

  Double cyclization of linear pentapeptide 3 by treatment with CsF in DMF at –5 °C gives a model bicyclic CODOE ring 2 of vancomycin in a one-pot fashion.

  在–5 °C下，使用CsF处理线性五肽3于DMF中，以一步法的方式得到万古霉素的模型双环CODOE环2。
• Solid Phase Synthesis of Vancomycin Mimics
  作者：Christopher J. Arnusch、Roland J. Pieters

  DOI：10.1002/ejoc.200300044

  日期：2003.8

  A solid phase synthesis of a model system of the DE ring system of vancomycin is described. The synthesis involved biocatalytic resolutions of unnatural amino acids, is compatible with conventional solid phase peptide synthesis and contains as the key step: an on-bead SNAr cyclization. Binding of a cyclic peptide to the carboxylate of N-Ac-D-Ala was demonstrated. (© Wiley-VCH Verlag GmbH & Co. KGaA

  描述了万古霉素 DE 环系统模型系统的固相合成。合成涉及非天然氨基酸的生物催化拆分，与传统的固相肽合成兼容，并包含关键步骤：珠上 SNAr 环化。证明了环肽与 N-Ac-D-Ala 的羧酸盐的结合。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
• First and Second Generation Total Synthesis of the Teicoplanin Aglycon
  作者：Dale L. Boger、Seong Heon Kim、Yoshiki Mori、Jian-Hui Weng、Olivier Rogel、Steven L. Castle、J. Jeffrey McAtee

  DOI：10.1021/ja003835i

  日期：2001.3.1

  Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide

  提供了导致替考拉宁苷元全合成的研究的全部细节。第一代方法的关键要素（来自组成氨基酸的 26 个步骤，总体为 1%）包括将 EFG 三肽前体偶联到常见的万古霉素/替考拉宁 ABCD 环系统和 16 元环的顺序 DE 大环化，形成二芳基醚通过邻氟硝基芳族化合物（80%，3:1 阻转异构体非对映选择）的酚盐亲核芳族取代，然后通过大环内酰胺化（66%）进行 14 元 FG 环闭合。随后的研究提供了更短、更会聚和高度非对映选择性的第二代全合成（22 步，总体 2%）。这是通过改变闭环的顺序来实现的，这样 FG 大环内酰胺化 (95%) 先于 EFG 三肽偶联到 ABCD 环系统和随后的 DE 环闭合。值得注意的是，通过在底物 57 上形成二芳基醚的 DE 大环化，后者是包含完整 FG 环系统的后一种方法中的关键中间体，发生特殊的非对映选择以形成天然阻转异构体 (>10:1, 76%)，没有问题 C(2
• Synthesis and binding studies of carboxylate binding pocket analogs of vancomycin
  作者：Roland J Pieters

  DOI：10.1016/s0040-4039(00)01270-3

  日期：2000.9

  Synthetic receptors based on the carboxylate binding pocket of vancomycin were synthesized. Using a UV binding assay, affinities of various cell wall related carboxylates were measured in organic solvents. Affinities in the 103–104 M−1 range were determined as well as almost equal affinities for acylated alanine and lactate. Introduction of additional hydrogen bonding donors or positive charges into

  合成了基于万古霉素的羧酸盐结合口袋的合成受体。使用紫外线结合测定法，在有机溶剂中测量了各种细胞壁相关羧酸盐的亲和力。确定了在10 3 –10 4 M -1范围内的亲和力以及与酰化的丙氨酸和乳酸几乎相等的亲和力。将额外的氢键供体或正电荷引入受体导致羧酸盐的亲和力增加。
• Design and Synthesis of Simple Macrocycles Active Against Vancomycin-ResistantEnterococci (VRE)
  作者：Yanxing Jia、Nianchun Ma、Zuosheng Liu、Michèle Bois-Choussy、Eduardo Gonzalez-Zamora、Adriano Malabarba、Cristina Brunati、Jieping Zhu

  DOI：10.1002/chem.200600137

  日期：2006.7.5

  ring-closure reaction is found to be sensitive to the peptide backbone and chemoselective cyclization (phenol versus primary amine) is achievable. Glycosylation of phenol was realized with freshly prepared 3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-deoxy-alpha-D-glucopyranosyl bromide under phase-transfer conditions. Minimum inhibitory concentrations for all of the derivatives are measured by using a standard

  设计并合成了模拟万古霉素结合口袋（DOE环）的16元间，对环烷。这些含有联芳基醚的大环的结构关键特征是（1）存在β-氨基-α-羟基酸或α，β-二氨基酸作为环肽的C端组分，以及（2）存在疏水性链或脂化的氨基葡萄糖在适当的位置。通过分子内亲核芳族取代反应（S（N）Ar）进行的环醚化被用作构建大环的关键步骤。发现该闭环反应的对映选择性对肽骨架敏感，并且可实现化学选择性环化（苯酚对伯胺）。用新鲜制备的3,4实现苯酚的糖基化，在相转移条件下的6-三-O-乙酰基-2-N-月桂酰基-2-氨基-2-脱氧-α-D-吡喃葡萄糖基溴化物。使用标准微量稀释测定法测量所有衍生物的最低抑菌浓度，并且发现其中某些化合物对敏感菌株和耐药菌株均具有有效的生物活性（MIC（最低抑菌浓度）= 4 microg mL（-1）对VRE ）。从这些初步的SAR研究中，可以预期，疏水性取代基的存在和大环的适当结构都需要使这一系列化合物