N-Boc-5(S)-tert-butyl-L-proline methyl ester | 185064-55-5

• 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
• 英文名称: N-Boc-5(S)-tert-butyl-L-proline methyl ester
• 英文别名: 1-O-tert-butyl 2-O-methyl (2S,5S)-5-tert-butylpyrrolidine-1,2-dicarboxylate
• CAS: 185064-55-5
• 化学式: C₁₅H₂₇NO₄
• 分子量: 285.384
• InChiKey: RWXRXJRQJMCONT-QWRGUYRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-Boc-5(S)-tert-butyl-L-proline methyl ester 在 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 48.0h， 以82%的产率得到(2S,5S)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸
  参考文献：
  名称：

  5-tert-Butylproline

  摘要：

  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.

  DOI：

  10.1021/jo9618738
• 作为产物：
  描述：

  (2S)-4-(methoxycarbonyl)-6,6-dimethyl-5-oxo-2-(tritylamino)heptanoic acid 在 palladium on activated charcoal sodium hydroxide 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 为溶剂， 生成 N-Boc-5(S)-tert-butyl-L-proline methyl ester
  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

• Conformationally rigid N-acyl-5-alkyl-l-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors
  作者：Erik A.A. Wallén、Johannes A.M. Christiaans、Taija J. Saarinen、Elina M. Jarho、Markus M. Forsberg、Jarkko I. Venäläinen、Pekka T. Männistö、Jukka Gynther

  DOI：10.1016/s0968-0896(03)00363-8

  日期：2003.8

  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.
• 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.