(S)-6,6-Dimethyl-5-oxo-2-(9-phenyl-9H-fluoren-9-ylamino)-heptanoic acid methylamide | 185142-33-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (S)-6,6-Dimethyl-5-oxo-2-(9-phenyl-9H-fluoren-9-ylamino)-heptanoic acid methylamide
• 英文别名: (2S)-N,6,6-trimethyl-5-oxo-2-[(9-phenylfluoren-9-yl)amino]heptanamide
• CAS: 185142-33-0
• 化学式: C₂₉H₃₂N₂O₂
• 分子量: 440.585
• InChiKey: RYFIYSIEUGHFAK-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 (S)-6,6-Dimethyl-5-oxo-2-(9-phenyl-9H-fluoren-9-ylamino)-heptanoic acid methylamide 在 苯甲醚 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 以92%的产率得到(S)-5-tert-Butyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid methylamide; compound with trifluoro-acetic acid
  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：

  L-N-(9-(9-phenylfluorenyl))glutamic acid γ-methylester 在 sodium hydroxide 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 反应 96.75h， 生成 (S)-6,6-Dimethyl-5-oxo-2-(9-phenyl-9H-fluoren-9-ylamino)-heptanoic acid methylamide
  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

文献信息

• 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.