(2S,4S)-N-Boc-4-羟基-3,3-二甲基吡咯烷-2-甲酸 | 174060-99-2

• 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,4S)-N-Boc-4-羟基-3,3-二甲基吡咯烷-2-甲酸
• 中文别名: (2S,4S)-N-叔丁氧羰基-4-羟基-3,3-二甲基吡咯烷-2-甲酸
• 英文名称: (4S)-4-hydroxy-3,3-dimethyl-pyrrolidine-(2S)-1,2-dicarboxylic acid 1-tert-butyl ester
• 英文别名: (4S)-1-(tert-Butoxycarbonyl)-4-hydroxy-3,3-dimethyl-L-proline；(2S,4S)-4-hydroxy-3,3-dimethyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid
• CAS: 174060-99-2
• 化学式: C₁₂H₂₁NO₅
• 分子量: 259.302
• InChiKey: KHLBNVGMWMAGJM-HTQZYQBOSA-N

物化性质

• 沸点：
  392.1±42.0 °C(Predicted)
• 密度：
  1.208

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  87.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,4S)-N-Boc-4-羟基-3,3-二甲基吡咯烷-2-甲酸 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 26.0h， 生成 (2S,4S)-1-Acetyl-4-hydroxy-3,3-dimethyl-pyrrolidine-2-carboxylic acid methylamide
  参考文献：
  名称：

  Alkyl 3-Position Substituents Retard the Isomerization of Prolyl and Hydroxyprolyl Amides in Water

  摘要：

  The influence of alkyl 3-position substituents on the rate of amide isomerization N-terminal to proline and hydroxyproline has been explored via the synthesis and analysis of (2S)-N-(acetyl)proline N'-methylamide (1), (2S,4R)- and (2S,4S)-N-acetyl-4-hydroxyproline N'-methylamides 2 and 3, and their respective 3,3-dimethyl analogues 4-6. The relative populations of the amide cis and trans isomers as well as the rates for cis-to-trans and trans-to-cis isomerization of 1-6 in water were ascertained by NMR spectroscopy and magnetization transfer experiments. The relative populations of free C-terminal and hydrogen-bonded amides in the gamma-turn conformation were also estimated by integrating the N-H stretch absorbances in the FT-IR spectra of 1 and 4 in CHCl3. In addition, the structure of the amide trans isomer of (2S,4S)-N-acetyl-3,3-dimethyl-4-hydroxyproline N'-methylamide (6) was determined in the solid state by X-ray crystallographic analysis. In prolyl peptides 1-6, the 3,3-dimethyl and hydroxyl substituents had little effect on the amide isomer equilibrium. A dramatic decrease in the rate of cis-to-trans amide isomerization was observed for N-acetyl-3,3-dimethylproline N'-methylamide (4), which exhibited a k(ct) nearly 7-fold slower than that of 1. Similar effects of the 3,3-dimethyl substituents were observed, albeit to a lesser degree, in the cases of the hydroxyprolyl peptides. The FT-IR data for 4 and X-ray data for 6 both demonstrated that the 3,3-dimethyl substituents restricted the proline psi dihedral angle and prevented the formation of a gamma-turn conformation, having a seven-membered hydrogen bond between the C-terminal amide NH and N-terminal amide carbonyl. Furthermore, restriction of the psi dihedral angle by the methyl groups was observed in systematic computational conformational analyses of 1-6, in which the psi and omega dihedral angles were rotated at 30 degrees intervals and the energies of the local minima were determined. Retardation of the rate of cis-to-trans amide isomerization in the dimethyl analogues may be attributed to steric interactions favoring a psi dihedral angle at which the C-terminal amide carbonyl destabilizes the transition state through Coulomb repulsion of either the developing nitrogen lone pair or the carbonyl oxygen of the pyramidalized N-terminal amide. The consequences of S-alkyl and 4-hydroxyl substituents on the rate of proline amide isomerization in water, which was observed to decrease in the order 1 approximate to 3 > 2 > 6 > 5 > 4, may result from influences on the psi, dihedral angle geometry, inductive effects, and intramolecular hydrogen bonding.

  DOI：

  10.1021/jo980673o
• 作为产物：
  描述：

  (2S)-3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester 在 palladium on activated charcoal lithium aluminium tetrahydride 、 氢气 作用下， 以 四氢呋喃 为溶剂， -78.0 ℃ 、506.62 kPa 条件下， 反应 48.5h， 生成 (2S,4S)-N-Boc-4-羟基-3,3-二甲基吡咯烷-2-甲酸
  参考文献：
  名称：

  Regioselective Enolization and Alkylation of 4-Oxo-N-(9-phenylfluoren-9-yl)proline:  Synthesis of Enantiopure Proline−Valine and Hydroxyproline−Valine Chimeras

  摘要：

  The regioselective enolization of 4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (5) followed by alkylation with different alkyl halides has been used to synthesize a variety of beta-alkylproline derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe(3))(2) and alkylation with iodomethane provided 3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (7a) in excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by hydrogenation in the presence of di-tert-butyl dicarbonate provided enantiopure (2S,4R)- and (2S,4S)-3,3-dimethyl-4-hydroxy-N-(BOC)prolines. 2. Hydroxyproline-valine chimeras (2S,4R)- and (2S,4S)-2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield. Deoxygenation of 3,3-dimethyl-4-hydroxy-N-(9-phenylfluoren-9-yl)proline benzyl esters 9 via their conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl-N-(9-phenylfluoren-9-yl)proline benzyl ester (11) in excellent yield. Hydrogenation of 11 with Pearlman's catalyst in the presence of di-tert-butyl dicarbonate then furnished (2S)-3,3-dimethyl-N-(BOC)proline (1) in the last step of an eight-step synthesis (41% overall yield) from hydroxyproline. Both proline-valine and hydroxyproline-valine chimeras 1 and 2 were designed to serve as tools for studying the conformational requirements of biologically active peptides.

  DOI：

  10.1021/jo9514984

文献信息

• [EN] HIV PROTEASE INHIBITORS, COMPOSITIONS CONTAINING THE SAME AND THEIR PHARMACEUTICAL USES<br/>[FR] INHIBITEURS DE LA PROTEASE DU VIH, COMPOSITIONS LES CONTENANT ET LEURS UTILISATIONS PHARMACEUTIQUES
  申请人：PFIZER

  公开号：WO2005026114A1

  公开（公告）日：2005-03-24

  This invention relates to a novel series of chemical compounds useful as Human immunodeficiency Virus (HIV) protease inhibitors and to the use of such compounds as antiviral agents. The invention further relates to pharmaceutical compositions containing such antiviral agents, and their uses and materials for their synthesis

  这项发明涉及一类新型化合物系列，可用作人类免疫缺陷病毒（HIV）蛋白酶抑制剂，以及将这些化合物用作抗病毒剂的用途。该发明还涉及含有这种抗病毒剂的药物组合物，以及它们的用途和合成材料。
• Regioselective Enolization and Alkylation of 4-Oxo-<i>N</i>-(9-phenylfluoren-9-yl)proline:  Synthesis of Enantiopure Proline−Valine and Hydroxyproline−Valine Chimeras
  作者：Raman Sharma、William D. Lubell

  DOI：10.1021/jo9514984

  日期：1996.1.1

  The regioselective enolization of 4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (5) followed by alkylation with different alkyl halides has been used to synthesize a variety of beta-alkylproline derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe(3))(2) and alkylation with iodomethane provided 3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (7a) in excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by hydrogenation in the presence of di-tert-butyl dicarbonate provided enantiopure (2S,4R)- and (2S,4S)-3,3-dimethyl-4-hydroxy-N-(BOC)prolines. 2. Hydroxyproline-valine chimeras (2S,4R)- and (2S,4S)-2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield. Deoxygenation of 3,3-dimethyl-4-hydroxy-N-(9-phenylfluoren-9-yl)proline benzyl esters 9 via their conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl-N-(9-phenylfluoren-9-yl)proline benzyl ester (11) in excellent yield. Hydrogenation of 11 with Pearlman's catalyst in the presence of di-tert-butyl dicarbonate then furnished (2S)-3,3-dimethyl-N-(BOC)proline (1) in the last step of an eight-step synthesis (41% overall yield) from hydroxyproline. Both proline-valine and hydroxyproline-valine chimeras 1 and 2 were designed to serve as tools for studying the conformational requirements of biologically active peptides.
• Alkyl 3-Position Substituents Retard the Isomerization of Prolyl and Hydroxyprolyl Amides in Water
  作者：Eric Beausoleil、Raman Sharma、Stephen W. Michnick、William D. Lubell

  DOI：10.1021/jo980673o

  日期：1998.9.1

  The influence of alkyl 3-position substituents on the rate of amide isomerization N-terminal to proline and hydroxyproline has been explored via the synthesis and analysis of (2S)-N-(acetyl)proline N'-methylamide (1), (2S,4R)- and (2S,4S)-N-acetyl-4-hydroxyproline N'-methylamides 2 and 3, and their respective 3,3-dimethyl analogues 4-6. The relative populations of the amide cis and trans isomers as well as the rates for cis-to-trans and trans-to-cis isomerization of 1-6 in water were ascertained by NMR spectroscopy and magnetization transfer experiments. The relative populations of free C-terminal and hydrogen-bonded amides in the gamma-turn conformation were also estimated by integrating the N-H stretch absorbances in the FT-IR spectra of 1 and 4 in CHCl3. In addition, the structure of the amide trans isomer of (2S,4S)-N-acetyl-3,3-dimethyl-4-hydroxyproline N'-methylamide (6) was determined in the solid state by X-ray crystallographic analysis. In prolyl peptides 1-6, the 3,3-dimethyl and hydroxyl substituents had little effect on the amide isomer equilibrium. A dramatic decrease in the rate of cis-to-trans amide isomerization was observed for N-acetyl-3,3-dimethylproline N'-methylamide (4), which exhibited a k(ct) nearly 7-fold slower than that of 1. Similar effects of the 3,3-dimethyl substituents were observed, albeit to a lesser degree, in the cases of the hydroxyprolyl peptides. The FT-IR data for 4 and X-ray data for 6 both demonstrated that the 3,3-dimethyl substituents restricted the proline psi dihedral angle and prevented the formation of a gamma-turn conformation, having a seven-membered hydrogen bond between the C-terminal amide NH and N-terminal amide carbonyl. Furthermore, restriction of the psi dihedral angle by the methyl groups was observed in systematic computational conformational analyses of 1-6, in which the psi and omega dihedral angles were rotated at 30 degrees intervals and the energies of the local minima were determined. Retardation of the rate of cis-to-trans amide isomerization in the dimethyl analogues may be attributed to steric interactions favoring a psi dihedral angle at which the C-terminal amide carbonyl destabilizes the transition state through Coulomb repulsion of either the developing nitrogen lone pair or the carbonyl oxygen of the pyramidalized N-terminal amide. The consequences of S-alkyl and 4-hydroxyl substituents on the rate of proline amide isomerization in water, which was observed to decrease in the order 1 approximate to 3 > 2 > 6 > 5 > 4, may result from influences on the psi, dihedral angle geometry, inductive effects, and intramolecular hydrogen bonding.