(2S,5R)-N-Boc-5-叔丁基吡咯烷-2-甲酸 | 185142-15-8

• 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
• 中文名称: (2S,5R)-N-Boc-5-叔丁基吡咯烷-2-甲酸
• 中文别名: (2S,5R)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸
• 英文名称: (2S,5R)-N-Boc-5-tert-butylproline
• 英文别名: (2S,5R)-N-(tert-butyloxycarbonyl)-5-tert-butylproline；Boc-5(R)-tert-butyl-L-proline；N-Boc-5(R)-tert-butyl-L-proline；(2S,5R)-N-(tert-butoxycarbonyl)-5-tert-butylproline；(2S,5R)-N-Boc-5-tert-butylpyrrolidine-2-carboxylic acid；(2S,5R)-5-tert-butyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid
• CAS: 185142-15-8
• 化学式: C₁₄H₂₅NO₄
• 分子量: 271.357
• InChiKey: WODLVEFJKWRNHB-VHSXEESVSA-N

物化性质

• 沸点：
  373.8±35.0 °C(Predicted)
• 密度：
  1.105

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,5R)-N-Boc-5-叔丁基吡咯烷-2-甲酸 在 palladium on activated charcoal 盐酸 、 氢气 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 38.0h， 生成 N-(tert-butoxycarbonyl)-L-alanyl-(2S,5R)-5-tert-butylproline
  参考文献：
  名称：

  序列对 5-叔丁基脯氨酰 VI 型 β-转角模拟物中肽几何结构的影响

  摘要：

  通过将 (2S,5R)-5-叔丁基脯氨酸 (5-(t)BuPro) 结合到一系列二肽和四肽中来检查序列对转弯几何形状的影响。(2S,5R)-5-叔丁基脯氨酸和脯氨酸分别引入 N-乙酰二肽 N'-甲基酰胺 1 和 2 的 C 端残基。这些类似物的构象分析也使用 NMR 和 CD 光谱进行作为X射线衍射检查控制脯氨酰胺的因素（本文中的术语“脯氨酰胺”是指由脯氨酰残基的吡咯烷氮和N端残基的羰基组成的叔酰胺）平衡并稳定 VI 型β-转角构象。如在 1c 的晶体结构中所见，具有芳香族残基 N-末端到脯氨酸的高顺式异构体群体被证明是由部分带正电荷的脯氨酰胺氮和芳香族 pi 系统之间的堆积相互作用引起的。通过改变 Xaa 处的氨基酸研究序列对 5-(t)BuPro-四肽 (Ac-Xaa-Yaa-5-(t)BuPro-Zaa-XMe, 13 和 14) 的脯氨酰酰胺平衡的影响、Yaa 和 Zaa 位置。获得高

  DOI：

  10.1021/ja012442w
• 作为产物：
  描述：

  (2S)-4-(methoxycarbonyl)-6,6-dimethyl-5-oxo-2-(tritylamino)heptanoic acid 在 palladium on activated charcoal lithium hydroxide 、 sodium hydroxide 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 为溶剂， 生成 (2S,5R)-N-Boc-5-叔丁基吡咯烷-2-甲酸
  参考文献：
  名称：

  Conformationally rigid N-acyl-5-alkyl-l-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors

  摘要：

  In the N-acyl-(L)-prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the L-prolyl group was replaced by different 5-alkyl-(L)-prolyl groups, resulting in a series of N-acyl-5-alkyl-(L)-prolyl-pyrrolidines. Since N-amides of 5-alkyl-(L)-prolines are conformationally more rigid than those of (L)-proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly. A similar effect was not observed for the 5(S)-tert-butyl group. In the series of compounds where the N-acyl group was a 4-phenylbutanoyl group, the 5(R)-tert-butyl, 5(R)-methyl and 5(S)-methyl groups did not have an effect on the potency [the 5(S)-tert-butyl group was not tested in this series]. As an additional effect, the 5-tert-butyl groups increased the log P of the compounds 1.5 log units, which might be beneficial when targeting the compounds to the brain. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00363-8

文献信息

• Use of Steric Interactions To Control Peptide Turn Geometry. Synthesis of Type VI β-Turn Mimics with 5-<i>tert</i>-Butylproline
  作者：Liliane Halab、William D. Lubell

  DOI：10.1021/jo990294a

  日期：1999.4.1

  DMSO, and water by proton NMR spectroscopy. Although the trans-amide isomer was favored in prolyl peptide 2, the Xaa-Pro peptide bond adopted preferably the cis-amide isomer in the case of 5-tert-butylprolyl peptide 1. Measurements of the influence of solvent and temperature on the chemical shift values for the amide proton signals of 1 in the cis-amide conformer indicated that the N'-methylamide was

  研究了空间相互作用对肽几何形状的影响，以开发出一种新型的产生VIa型β-turn模拟物的方法。（2S，5R）-5-叔丁基脯氨酸和L-脯氨酸分别引入N-（乙酰基）二肽N'-甲基酰胺1和2的C端残基。脯氨酰顺酰胺和反酰胺的相对种群通过质子NMR光谱法在氯仿，DMSO和水中测量二肽1和2中的异构体。尽管脯氨酰肽2倾向于使用反酰胺异构体，但在5-叔丁基脯氨酰肽1的情况下，Xaa-Pro肽键优选采用顺酰胺异构体。测量溶剂和温度对化学位移的影响顺式酰胺构象的酰胺质子信号值为1表示N' -甲基酰胺与乙酰胺羰基以VIaβ-转构型进行氢键键合。通过X射线衍射分析固态的N-（乙酰基）亮氨酰-5-叔丁基脯氨酸N'-甲基酰胺（1d）显示顺式酰胺构象异构体采用了中心i + 1和i的几何特征+ 2个理想VIa型β-残基的残基。与脯氨酰肽2b和2d相比，N-（乙酰基）丙氨酰和N-（乙酰基）亮氨酰基-5-叔丁基脯氨酸N'
• Improved synthesis of (2S,5S)-5-tert-butylproline
  作者：Liliane Halab、Laurent Bélec、William D Lubell

  DOI：10.1016/s0040-4020(01)00535-x

  日期：2001.7

  oline (1) was synthesized by an improved procedure featuring the conversion of (2S)-1-tert-butyldimethylsiloxy-2-N-(PhF)amino-5-oxo-6,6-dimethylheptane (16) into its corresponding imino alcohol followed by directed hydride delivery to reduce the imine functionality with a 95:5 diastereoselectivity. Ketone 16 was obtained from methyl 2-N-(PhF)amino-5-oxo-6,6-dimethylheptanoate (13), a previously reported

  （2 S，5 S）-N -Boc-5-叔丁基脯氨酸（1）通过一种改进的方法合成，该方法的特征是将（2 S）-1-叔丁基二甲基甲硅烷氧基-2- N-（PhF）氨基-将5-氧代-6,6-二甲基庚烷（16）转化为其相应的亚氨基醇，然后进行定向氢化物传递，以95：5的非对映选择性降低亚胺官能度。酮16是从2- N-（PhF）氨基-5-氧代6,6-二甲基庚酸甲酯（13）获得的，后者是先前报道的合成（2 S，5 R）-5-的前体。叔丁基脯氨酸，通过还原成其相应的二醇，对伯醇进行选择性保护，并对仲醇进行氧化。该路线提供了适用于肽化学的对映体纯度> 96％的（2 S，5 S）-N - Boc -5-叔丁基脯氨酸（1），来自酮13的总收率为39％。
• Compounds having prolyl oligopeptidase inhibitory activity
  申请人：Gynther Jukka

  公开号：US20060229254A1

  公开（公告）日：2006-10-12

  A compound of formula (I), wherein X, R 1 , R 2 and R 3 are as defined in the disclosure, or a pharmaceutically acceptable salt or ester thereof, useful as a prolyl oligopeptidase inhibitor. The compounds can be used for the treatment of diseases or conditions where prolyl oligopeptidase inhibitors are indicated to be effective, for example for the treatment of neurodegenerative diseases, such as Alzheimer's disease and senile dementia.

  式(I)的化合物，其中X、R1、R2和R3如所披露的定义，或其药学上可接受的盐或酯，可用作脯氨酰寡肽酶抑制剂。这些化合物可用于治疗需要脯氨酰寡肽酶抑制剂具有疗效的疾病或情况，例如用于治疗神经退行性疾病，如阿尔茨海默病和老年性痴呆症。
• An introduction of a pyridine group into the structure of prolyl oligopeptidase inhibitors
  作者：Elina M. Jarho、Jarkko I. Venäläinen、Juha Juntunen、A. Leena Yli-Kokko、Jouko Vepsäläinen、Johannes A.M. Christiaans、Markus M. Forsberg、Tomi Järvinen、Pekka T. Männistö、Erik A.A. Wallén

  DOI：10.1016/j.bmcl.2006.08.029

  日期：2006.11

  A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-L-prolyl group at the P2 position, good lipophilicity can be achieved. (c) 2006 Elsevier Ltd. All rights reserved.
• 5-<i>tert</i>-Butylproline
  作者：Eric Beausoleil、Benoît L'Archevêque、Laurent Bélec、Mohamed Atfani、William D. Lubell

  DOI：10.1021/jo9618738

  日期：1996.1.1

  Steric effects on the isomer equilibrium of amides N-terminal to proline can be explored with 5-alkylprolines having bulky 5-position substituents. Enantiopure 5-tert-butylprolines were thus synthesized from glutamic acid via an acylation/diastereoselective reductive amination sequence. Double deprotonation of gamma-methyl N-(PhF)glutamate (2) with LiN(SiMe(3))(2) and C-acylation with pivaloyl chloride provided beta-keto ester 3, which upon gamma-ester hydrolysis and decarboxylation gave delta-oxo-alpha-[N-(PhF)amino]heptanoic acid (4). Syntheses of (2S,5R)- and (2R, 5S)-N-(BOC)-5-tert-butylprolines ((2S,5R)-1 and (2R,5S)-1) were accomplished by catalytic hydrogenation of their respective (2S)- and (2R)-methyl delta-ore-alpha-[N-(PhF)amino]heptanoates ((2S)-5a and (2R)-5a) in methanol with di-tert-butyl dicarbonate followed by chromatography and ester hydrolysis with potassium trimethylsilanolate. The 5-tert-butylproline cis-diastereomers were proven to be of >99% enantiomeric purity after their conversion to diastereomeric alpha-methylbenzylamides 10. Good diastereoselectivity in favor of the trans-diastereomer was observed when (2S,5S)-5-tert-butylproline was synthesized from (2S)-delta-oxo-alpha-[N-(PkF)amino]heptanoate ((2S)-4) by solvolysis of the PhF group in trifluoroacetic acid and subsequent reduction of 5-tert-butyl-Delta 5-dehydroproline (11) with tetramethylammonium triacetoxyborohydride; however, imino acid 11 was shown to be configurationally labile and racemized under acidic conditions. 5-tert-Butyl-Delta 5-dehydroproline N'-methylamide 15 was configurationally stable in acid, yet preliminary attempts to reduce 15 favored cis-diastereomer 16. Alternatively, enantiopure trans-diastereomer, (2R,5R)-methyl N-(BOC)-5-tert-butylprolinate (9) was prepared by epimerization of(2S,5R)-9. In summary, this synthetic methodology now provides access to all four enantiopure 5-tert-butylproline isomers from inexpensive L- and D-glutamate as chiral educts.