tert-butyl (5S)-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenyl-(E)hexenoate | 488760-73-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (5S)-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenyl-(E)hexenoate
• 英文别名: tert-butyl (5S)-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenyl-(E)-2-hexenoate；tert-butyl (E,5S)-5-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-6-phenylhex-2-enoate
• CAS: 488760-73-2
• 化学式: C₂₁H₂₉NO₅
• 分子量: 375.465
• InChiKey: CMGREFGEKJLANL-DBTPVHCXSA-N

物化性质

• 熔点：
  68-70 °C
• 沸点：
  510.2±50.0 °C(Predicted)
• 密度：
  1.092±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (5S)-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenyl-(E)hexenoate 在 palladium on activated charcoal 氢气 、 lithium tri-t-butoxyaluminum hydride 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 tert-butyl (4R,5S)-5-[N-(tert-butoxycarbonyl)amino]-4-hydroxy-6-phenyl-hexanoate
  参考文献：
  名称：

  Stereoselective Synthesis of Photoreactive Peptidomimetic γ-Secretase Inhibitors

  摘要：

  The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO2-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.

  DOI：

  10.1021/jo0486948
• 作为产物：
  描述：

  N-叔丁氧羰基-L-苯丙氨酸甲酯 在 potassium carbonate 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 tert-butyl (5S)-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenyl-(E)hexenoate
  参考文献：
  名称：

  Stereoselective Synthesis of Photoreactive Peptidomimetic γ-Secretase Inhibitors

  摘要：

  The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO2-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.

  DOI：

  10.1021/jo0486948

文献信息

• Diastereoselective Reduction of a Chiral <i>N</i>-Boc-Protected δ-Amino-α,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic
  作者：Jon Våbenø、Magnus Brisander、Tore Lejon、Kristina Luthman

  DOI：10.1021/jo020442o

  日期：2002.12.1

  The readily available N-Boc-protected delta-amino alpha,beta-unsaturated gamma-keto ester 1 was diastereoselectively reduced to the corresponding alcohols 2 and 3, using boron- and aluminum-based reducing reagents. Reduction reactions were successful and resulted in anti/syn ratios of alcohols of >95:5 (80% yield), using LiAlH(O-t-Bu)(3) in EtOH at -78degreesC under chelation control, and 5:95 (98% yield), using NB-Enantride in THF at -78degreesC under Felkin-Anh control.
• Dipeptidomimetic Ketomethylene Isosteres as Pro-moieties for Drug Transport via the Human Intestinal Di-/Tripeptide Transporter hPEPT1:  Design, Synthesis, Stability, and Biological Investigations
  作者：Jon Våbenø、Carsten Uhd Nielsen、Truls Ingebrigtsen、Tore Lejon、Bente Steffansen、Kristina Luthman

  DOI：10.1021/jm040780c

  日期：2004.9.1

  Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available alpha,beta-unsaturated gamma-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic. The stability, the affinity for the di-/tripeptide transporter hPEPT1, and the transepithelial transport properties of the model prodrugs were investigated. ValPsi[COCH2]-Asp(OBn) was the compound with highest chemical stability in buffers at pH 6.0 and 7.4, with half-lives of 190 and 43 h, respectively. All five compounds showed high affinity for hPEPT1 (K-i values < 1 mM), and PhePsi[COCH2]Asp(OBn) and ValPsi[COCH2]Asp(OBn) had the highest affinities with K-i values of 68 and 19 muM, respectively. Am hPEPT1-mediated transport component was demonstrated for the transepithelial transport of three compounds, a finding that was corroborated by hPEPT1-mediated intracellular uptake. The results indicate that the stabilized Phe-Asp and Val-Asp derivatives are promising pro-moieties in a prodrug approach targeting hPEPT1.
• Phe-Gly Dipeptidomimetics Designed for the Di-/Tripeptide Transporters PEPT1 and PEPT2:  Synthesis and Biological Investigations
  作者：Jon Våbenø、Tore Lejon、Carsten Uhd Nielsen、Bente Steffansen、Weiqing Chen、Hui Ouyang、Ronald T. Borchardt、Kristina Luthman

  DOI：10.1021/jm031022+

  日期：2004.2.1

  A series of five Phe-Gly dipeptidomimetics containing different amide bond replacements have been synthesized in a facile way from the readily available unsaturated ketoester 1, and their affinities for the di-/tripeptide transporters hPEPT1 (Caco-2 cells) and rPEPT2 (SKPT cells) were tested. The compounds contained the amide bond isosteres ketomethylene (2a), (R)- and (S)-hydroxyethylidene (3a and 4a), and (R)- and (S)-hydroxyethylene (5a and 6a) to provide information on the conformational and stereochemical requirements for hPEPT1 and rPEPT2 affinity. The affinity studies showed that for rPEPT2 there is no significant difference in affinity between the ketomethylene isostere 2a and the natural substrate Phe-Gly (K-i values of 18.8 and 14.6 muM, respectively). Also the affinities for hPEPT1 are in the same range (K-i values of 0.40 and 0.20 mM, respectively). This corroborates earlier findings that the amide bond as such is not essential for binding to PEPTX, but the results also reveal possible differences in the binding of ketomethylene isosteres to hPEPT1 and rPEPT2. The trans-hydroxyethylidene and hydroxyethylene isosteres proved to be poor substrates for PEPTX. These results provide new information about the importance of flexibility and of the stereochemistry at the C-4-position for this class of compounds. Furthermore, the intracellular uptake of 2a-4a in Caco-2 cells was investigated, showing a 3-fold reduction of the uptake of 2a in the presence of the competetive inhibitor Gly-Pro, indicating contribution from an active transport component. No active uptake of 3a and 4a was observed. Transepithelial. transport studies also indicated active transport of 2a across Caco-2 monolayers.
• Stereoselective Synthesis of Photoreactive Peptidomimetic γ-Secretase Inhibitors
  作者：Jiong Chun、Ye Ingrid Yin、Guangli Yang、Leonid Tarassishin、Yue-Ming Li

  DOI：10.1021/jo0486948

  日期：2004.10.1

  The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO2-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.