(2S,4S)-4-Hydroxy-3,3-dimethyl-2-methylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester | 213882-60-1

• 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: (2S,4S)-4-Hydroxy-3,3-dimethyl-2-methylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (2S,4S)-4-hydroxy-3,3-dimethyl-2-(methylcarbamoyl)pyrrolidine-1-carboxylate
• CAS: 213882-60-1
• 化学式: C₁₃H₂₄N₂O₄
• 分子量: 272.345
• InChiKey: YFSUHIBOFUNTTC-RKDXNWHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,4S)-4-Hydroxy-3,3-dimethyl-2-methylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以98%的产率得到(2S,4S)-4-Hydroxy-3,3-dimethyl-pyrrolidine-2-carboxylic acid methylamide; hydrochloride
  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：

  盐酸甲胺 、 (2S,4S)-N-Boc-4-羟基-3,3-二甲基吡咯烷-2-甲酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 24.0h， 生成 (2S,4S)-4-Hydroxy-3,3-dimethyl-2-methylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester
  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

文献信息

• 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.