(3s,6s,8as)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯 | 159303-54-5

• 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
• 中文名称: (3s,6s,8as)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯
• 中文别名: (3S,6S,8AS)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯
• 英文名称: (3S,6R,9S)-1-aza-3-t-butoxycarbonylamino-9-carbomethoxybicyclo[4.3.0]nonane
• 英文别名: (3S,6S,9S) methyl 2-oxo-3-[N-(t-butoxycarbonyl)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate；(3S,6S,9S)-methyl 2-oxo-3--1-azabicyclo<4.3.0>nonane-9-carboxylate；methyl (3S,6S,8aS)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylate；(3S,6S,8aS)-6-((tert-butoxycarbonyl)amino)methyl-5-oxoindole-3-carboxylic acid methyl ester；(3S,6S,8aS)-Methyl 6-((tert-butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylate；methyl (3S,6S,8aS)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate
• CAS: 159303-54-5
• 化学式: C₁₅H₂₄N₂O₅
• 分子量: 312.366
• InChiKey: RBDIIUAKDGDILT-DCAQKATOSA-N

物化性质

• 沸点：
  460.5±34.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3s,6s,8as)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯 在 lithium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以92%的产率得到(3S,6s,8as)-6-(叔丁氧基羰基氨基)-5-氧代八氢吲哚嗪-3-羧酸
  参考文献：
  名称：

  配对的氮杂氨基脯氨酸脯氨酸和吲哚西酮酮氨基酸残基用于肽模拟：前列腺素F2α受体变构调节剂的构想可延迟早产。

  摘要：

  利用氮杂-氨基酰基脯氨酸和吲哚izidinone残基的组合模拟肽已被用于开发前列腺素F2α受体的变构调节剂。系统研究N末端苯乙酰基部分和中央转向二肽残基的构象和侧链功能已证明调节剂活性和拓扑之间的敏感关系。在以脂多糖治疗的小鼠早产模型中对aza-Gly-Pro和aza-Phe-Pro类似物2a和2b的检查表明，它们能够显着延长平均分娩时间（> 20小时），从而为延迟早产提供了新的原型。 。

  DOI：

  10.1021/acs.jmedchem.9b00056
• 作为产物：
  描述：

  1-carbomethoxy-5-methoxy-L-proline methyl ester 在 palladium on activated charcoal Grubbs catalyst first generation 、 三氯化铝 、 四丁基氟化铵 、 氢气 、 四氯化锡 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 63.0h， 生成 (3s,6s,8as)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯
  参考文献：
  名称：

  阳极酰胺氧化/烯烃复分解策略：开发统一的方法合成双环内酰胺肽模拟物。

  摘要：

  与建立用于内分泌激素TRH的约束肽模拟物的努力有关，已经开发了构建双环内酰胺肽构件的一般策略。该策略使用阳极酰胺氧化来选择性官能化脯氨酸，然后进行烯烃复分解以建立所需的内酰胺​​约束。所描述的途径提供了一种用于合成具有七元和八元环内酰胺约束的完全官能化的TRH类似物以及在中心氨基酸上没有侧链的六元和七元环内酰胺类似物的单一方法。

  DOI：

  10.1016/s0040-4020(00)00856-5

文献信息

• Synthesis of Conformationally Constrained Dipeptide Mimetics with Azabicyclo[4,3,0]nonanone and Azabicyclo[5,3,0]decanone Scaffolds
  作者：Wanlin Xi、Lei Du、Liping Zhang、Haiying Sun

  DOI：10.1021/acs.joc.0c00399

  日期：2020.8.7

  and efficient method for the synthesis of azabicyclo[4,3,0]nonanone and azabicyclo[5,3,0]decanone amino acid derivatives was developed with the palladium-catalyzed coupling of intermediates 9 and 10 with BocNH2 and Boc2NH and the following reduction of the C–C double bond by hydrogenation as the key steps. The exploration of the synthesis of C6-substituted dipeptide mimetics from 9 and 10 using Suzuki

  利用钯催化的中间体9和10与BocNH 2和Boc 2的偶合偶联反应，开发了一种合成氮杂双环[4,3,0]壬酮和氮杂双环[5,3,0]癸烷氨基酸衍生物的通用有效方法。NH和随后通过氢化还原C–C双键是关键步骤。还进行了使用Suzuki偶联作为关键反应从9和10合成C 6取代的二肽模拟物的探索。
• 一种基于氮杂双环[X，Y，0]烷酮骨架的二肽 模拟物及其制备方法
  申请人：中国药科大学

  公开号：CN111560017B

  公开（公告）日：2021-12-07

  本发明公开了一种基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物及其制备方法，该二肽模拟物具有如下结构：其中，n＝1‑4；R1为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR3；R2和R3为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；所述取代基均指烷基、环烷基、芳基或杂环芳基，并提供该二肽模拟物的制备方法，本发明的二肽模拟物代谢稳定性好、生物利用度高、透膜能力强，制备方法路线较短、效率较高且具有通用性。
• An efficient approach to asymmetric synthesis of dipeptide β-turn mimetics: indolizidinone amino acids
  作者：Wei Wang、Chiyi Xiong、Victor J Hruby

  DOI：10.1016/s0040-4039(01)00409-9

  日期：2001.4

  Azabicyclo[X.Y.0] alkane amino acids are rigid dipeptide P-turn mimetics with great potential applications for drug discovery. The lack of efficient methods to synthesize these compounds is a major bottleneck in this field. Herein we report an efficient approach to the enantiopure synthesis of (3S,6S,9S) and (3R,6R,9R) methyl 2-oxo-3-[N-(Boc/Cbz)amino]-1-azabicyclo[4,3,0]nonane-9-carboxylates 1. In this approach, the key intermediates 5a and 5b with different stereochemical configurations were efficiently constructed from the same precursor in high stereoselectivity via asymmetric hydrogenations using (S,S) or (R,R) Et-DUPHOS, Rh(I)-based catalysts. The process, starting from inexpensive diethyl 1,3-acetonedicarboxylate 2, can allow for the practical synthesis of this class of compounds. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids
  作者：Henry-Georges Lombart、William D. Lubell

  DOI：10.1021/jo961872f

  日期：1996.1.1

  An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of beta-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-alcohol 7a, which upon mesylation, and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-indolizidinone methyl ester 12 with NaN(SiMe(3))(2) and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.
• Synthesis of Enantiopure .alpha.,.omega.-Diamino Dicarboxylates and Azabicycloalkane Amino Acids by Claisen Condensation of .alpha.-[N-(Phenylfluorenyl)amino] Dicarboxylates
  作者：Henry-Georges Lombart、William D. Lubell

  DOI：10.1021/jo00100a008

  日期：1994.10

  Enantiomerically pure (3S,6S,9S)-2-oxo-3-(N-BOC-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid ((3S,6S,9S)-1) was prepared in 39% overall yield from alpha-tert-butyl gamma-methyl N-(9-(9-phenylfluorenyl))glutamate (5) using a Claisen condensation/reductive amination/lactam cyclization sequence.