(2S,3R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylpent-4-enoate | 260270-95-9

• 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: (2S,3R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylpent-4-enoate
• 英文别名: tert-butyl (2S,3R)-2-{[(benzyloxy)carbonyl]amino}-3-methyl-4-pentenoate；tert-Butyl (2S,3R)-2-Benzyloxycarbonylamino-3-methyl4-pentenoate；tert-butyl (2S,3R)-2-benzyloxycarbonylamino-3-methyl-4-pentenoate；tert-butyl (2S,3R)-3-methyl-2-(phenylmethoxycarbonylamino)pent-4-enoate
• CAS: 260270-95-9
• 化学式: C₁₈H₂₅NO₄
• 分子量: 319.401
• InChiKey: JHZNXYGIHYDFFW-HIFRSBDPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 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：

  (2S,3R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylpent-4-enoate 在 Lindlar's catalyst 吡啶 、 叠氮化锂 、 thexylborane 、 TEA 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 50.0 ℃ 、206.85 kPa 条件下， 反应 36.0h， 生成 tert-butyl (2S,3R)-2-{[(benzyloxy)carbonyl]amino}-5-amino-3-methylpentanoate
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654
• 作为产物：
  描述：

  (S)-3-Methyl-2-(2,2,2-trifluoro-acetylamino)-pent-4-enoic acid 在 sodium hydroxide 作用下， 以 甲苯 为溶剂， 反应 9.0h， 生成 (2S,3R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylpent-4-enoate
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654

文献信息

• Formamide compounds as therapeutic agents
  申请人：Glaxo Wellcome Inc.

  公开号：US06191150B1

  公开（公告）日：2001-02-20

  A family of compounds having the general structural formula where W is a reverse hydroxamic acid group, and R1, R2, R3, R4, R5 and R6 are as described in the specification, or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

  具有一般结构式的化合物家族，其中W是一个反向羟肟酸基团，而R1、R2、R3、R4、R5和R6如规范中所述，或其药学上可接受的盐、溶剂化合物、生物水解酯、生物水解酰胺、亲和试剂或其前药。
• 具有手性的3-取代的3-乙烯基-2-氨基丙酸酯及其制备方法
  申请人：上海健康医学院

  公开号：CN109438269A

  公开（公告）日：2019-03-08

  本发明提供了一种具有手性的3‑取代的3‑乙烯基‑2‑氨基丙酸酯，结构式如下：本发明还提供了上述合成3‑取代的3‑乙烯基‑2‑氨基丙酸酯的方法，其反应路线如下：本发明具有底物适用性强，反应条件温和，操作简单，合成成本低等优点，仅需一步反应即可实现具有连续手性中心的3‑取代的3‑乙烯基‑2‑氨基丙酸酯的立体发散性合成。本发明的产物可以直接应用到具有强抗炎活性的海洋天然产物Hal ipeptin A的重要手性氨基酸片段的选择性合成中去，将原有工艺大幅缩短。
• Enantioselective and Diastereodivergent Access to α-Substituted α-Amino Acids via Dual Iridium and Copper Catalysis
  作者：Jiacheng Zhang、Xiaohong Huo、Bowen Li、Zhouli Chen、Yashi Zou、Zhenliang Sun、Wanbin Zhang

  DOI：10.1002/adsc.201801148

  日期：2019.3.5

  and chiral Cu‐Phox complex combination allows for access to all four stereoisomers from the same starting materials with excellent enantioselectivity and diastereoselectivity (up to >99% ee and >20:1 dr). Significantly, this method provides a stereodivergent access to 2‐amino‐3‐methylpent‐4‐acid ester, an important fragment for the synthesis of Halipeptin A.

  本文报道的工作描述了双金属催化剂体系在烯丙基取代反应中的应用实例。新亲核试剂的开发以及对映异构和非对映异构选择性的控制是该领域的主要研究课题。在温和的反应条件下，无活性前手性亲核试剂的双重Ir / Cu催化的烯丙基烷基化反应已实现了反应性和非对映选择性的提高。此外，金属环铱配合物和手性Cu-Phox配合物的选择允许从相同的起始原料获得所有四种立体异构体，具有出色的对映选择性和非对映选择性（高达> 99％ee和> 20：1 dr）。重要的是，这种方法可以立体异构地获得2-氨基-3-甲基戊-4-酸酯
• Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)
  作者：Michael H. Rabinowitz、Robert C. Andrews、J. David Becherer、D. Mark Bickett、Dulce G. Bubacz、James G. Conway、David J. Cowan、Micheal Gaul、Kimberly Glennon、Millard H. Lambert、M. Anthony Leesnitzer、Darryl L. McDougald、Marcia L. Moss、David L. Musso、Michele C. Rizzolio

  DOI：10.1021/jm0102654

  日期：2001.11.1

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.