(S)-phenyl(pyrrolidin-2-yl)methanone | 771437-08-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-phenyl(pyrrolidin-2-yl)methanone
• 英文别名: (2S)-2-benzoylpyrrolidine；phenyl-[(2S)-pyrrolidin-2-yl]methanone
• CAS: 771437-08-2
• 化学式: C₁₁H₁₃NO
• 分子量: 175.23
• InChiKey: JNMOJXSLHIDBDW-JTQLQIEISA-N

物化性质

• 沸点：
  293.3±33.0 °C(Predicted)
• 密度：
  1.083±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (S)-phenyl(pyrrolidin-2-yl)methanone 在 三乙胺 、 乙酰氯 作用下， 以 四氢呋喃 为溶剂， 生成 4-chloro-3-(2-(phenylamido)pyrrolidinyl)pyridine-1-oxide
  参考文献：
  名称：

  手性 4-芳基吡啶-N-氧化物亲核催化剂：设计、合成和在酰化动态动力学拆分中的应用

  摘要：

  合理设计、合成了一种高效的手性 4-芳基吡啶-N-氧化物 (ArPNO) 亲核有机催化剂，并将其应用于唑类、醛类和酸酐的酰化动态动力学拆分。当使用手性吡啶-N-氧化物作为酰基转移催化剂时，吡啶的 C-4 位应始终存在二烷基氨基的限制被克服，从而允许该位置的结构多样性。在 5 mol% 3,5-二甲基苯基衍生的 ArPNO 催化剂存在下，以高达 93% 的产率、>20:1 rr 和 99% ee 获得相应的 2,5-二取代四唑半氨基酯。其他N-杂芳烃，包括取代的吡唑、咪唑、嘌呤、苯并咪唑和苯并三唑，也是合适的底物。通过对照实验和密度泛函理论计算的机理研究表明，形成了酰氧基吡啶鎓阳离子，唑半胺与酰氧基吡啶鎓阳离子的亲核取代是速率决定步骤。此外，吡啶-N-氧化物中氧的亲核能力高于吡啶中氮的亲核能力。这项工作为利用吡啶环的 C-4 位提供了一种有效的方法，从而可以开发出更多样化的手性 4-取代吡啶-N-氧化物作为有效的亲核有机催化剂。

  DOI：

  10.1021/acscatal.1c04923
• 作为产物：
  描述：

  N-(叔丁氧基羰基)-L-脯氨酸-N′-甲氧基-N′-甲酰胺 在 碘 、 magnesium 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.5h， 生成 (S)-phenyl(pyrrolidin-2-yl)methanone
  参考文献：
  名称：

  Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes

  摘要：

  Current molecular hypotheses have not yet delivered marketable treatments for Alzheimer's disease (AD), arguably due to a lack of understanding of AD biology and an overreliance on conventional drug modalities. Protein-protein interactions (PPIs) are emerging drug targets, which show promise for the treatment of, e.g., cancer, but are still underexploited for treating neurodegenerative diseases. 14-3-3 binding to phosphorylated Tau is a promising PPI drug target based on its reported destabilizing effect on microtubules, leading to enhanced neurofibrillary tangle formation as a potential cause of AD-related neurodegeneration. Inhibition of 14-3-3/Tau may therefore be neuroprotective. Previously, we reported the structure-guided development of modified peptide inhibitors of 14-3-3/Tau. Here, we report further efforts to optimize the binding mode and activity of our modified Tau peptides through a combination of chemical synthesis, biochemical assays, and X-ray crystallography. Most notably, we were able to characterize two different high-affinity binding modes, both of which inhibited 14-3-3-binding to full-length PKA-phosphorylated Tau protein in vitro as measured by NMR spectroscopy. Our findings, besides producing useful tool inhibitor compounds for studying 14-3-3/Tau, have enhanced our understanding of the molecular parameters for inhibiting 14-3-3/Tau, which are important milestones toward the establishment of our 14-3-3 PPI hypothesis.

  DOI：

  10.1021/acschemneuro.8b00118

文献信息

• [EN] PROCESS FOR THE PREPARATION OF CHIRAL PYROLLIDINE-2-YL- METHANOL DERIVATIVES<br/>[FR] PROCÉDÉ DE PRÉPARATION DE DÉRIVÉS CHIRAUX DE PYROLLIDINE-2-YL-MÉTHANOL
  申请人：HOFFMANN LA ROCHE

  公开号：WO2018153820A1

  公开（公告）日：2018-08-30

  The invention relates to a novel process for the preparation of a chiral pyrollidine-2-yl-methanol derivative or a salt thereof of the formula (I), wherein R1 is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy or halogen. The synthesis proceeds through an intermediate Weinreb amide, which is reacted with a Grignard reagent and hydrogenated. The chiral pyrollidine-2-yl-methanol derivatives of the formula (I) are versatile building blocks in the synthesis of pharmacologically active compounds, such as for the stereospecific synthesis of oligonucleotides carrying chiral phosphonate moieties.

  该发明涉及一种新型制备手性吡咯烷基-2-甲醇衍生物或其盐的方法，其化学式为（I），其中R1为芳基或杂芳基，且芳基或杂芳基可选择地被C1-4-烷基、卤代C1-4-烷基、C1-4-烷氧基或卤素取代。合成过程通过中间体酰胺酯与格氏试剂反应并进行氢化。化学式（I）中的手性吡咯烷基-2-甲醇衍生物是合成药理活性化合物的多功能构建块，例如用于携带手性膦酸酯基团的寡核苷酸的立体选择性合成。
• Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors
  作者：Dana Ferraris、Yao-Sen Ko、David Calvin、Tiffany Chiou、Susan Lautar、Bert Thomas、Krystyna Wozniak、Camilo Rojas、Vincent Kalish、Sergei Belyakov

  DOI：10.1016/j.bmcl.2004.08.057

  日期：2004.11

  In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S1' binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG)

  在本文中，讨论了两类基于亲电子试剂的二肽基肽酶IV（DPP IV）抑制剂，酮吡咯烷和酮氮杂环丁烷的合成和构效关系（SAR）。这些系列的SAR表明，2-噻唑，2-苯并噻唑和2-吡啶基酮是针对DPP IV效力的最佳S1'结合基团。此外，环己基甘氨酸（CHG）和八氢吲哚羧酸酯（OIC）均是每个系列中最有效的S2结合基团。在中心环的α位的立体化学与酮吡咯烷系列中的效力有关，但与酮氮杂环丁烷系列中的效力无关。最后，酮氮杂环丁烷比相应的酮吡咯烷烷显示出增强的稳定性，同时保持它们的效力。实际上，
• New Prolyl Oligopeptidase Inhibitors Developed from Dicarboxylic Acid Bis(<scp>l</scp>-prolyl-pyrrolidine) Amides
  作者：Erik A. A. Wallén、Johannes A. M. Christiaans、Elina M. Jarho、Markus M. Forsberg、Jarkko I. Venäläinen、Pekka T. Männistö、Jukka Gynther

  DOI：10.1021/jm030811o

  日期：2003.10.1

  Isophthalic acid bis(L-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl. group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)(hydroxyacetyl)pyrrolidinyl groups.