(+)-(S)-methyl 4-methyl-2-(picolinamido)pentanoate | 189341-89-7

• 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: (+)-(S)-methyl 4-methyl-2-(picolinamido)pentanoate
• 英文别名: methyl picolinoyl-L-leucinate；methyl (2S)-4-methyl-2-(pyridine-2-carbonylamino)pentanoate
• CAS: 189341-89-7
• 化学式: C₁₃H₁₈N₂O₃
• 分子量: 250.298
• InChiKey: KWSGRPCRPLXDMG-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  68.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+)-(S)-methyl 4-methyl-2-(picolinamido)pentanoate 在 N,N-二异丙基乙胺 、 lithium hydroxide 、 O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 methyl picolinoyl-L-leucyl-L-alaninate
  参考文献：
  名称：

  Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D₂R

  摘要：

  This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([H-3]-NPA) at dopamine D-2 receptors (D2R). Methyl picolinoyl-L-valyl-L-alaninate (compound 6b) produced a statistically significant increase in the maximal [H-3]-NPA response at 0.01 nM (11.9 +/- 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 +/- 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 +/- 7.1% for 6b vs 15.4 +/- 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of 6b show EC50 (0.33 +/- 0.21 mu M for 6b vs 0.17 +/- 0.07 pM for MIF-1) and E-max (86.0 +/- 5.4% for 6b vs 93.6 +/- 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic 6b was tested for agonist activity at the human D2R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D2R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 mu M. Conformational energy minimization for 6b shows that this peptidomimetic cannot adopt the postulated type-II beta-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.

  DOI：

  10.1021/acschemneuro.9b00259
• 作为产物：
  描述：

  L-亮氨酸 在 4-二甲氨基吡啶 、 氯化亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 生成 (+)-(S)-methyl 4-methyl-2-(picolinamido)pentanoate
  参考文献：
  名称：

  多环氮杂环丁烷和吡咯烷通过钯催化的未激活的C（sp3）–H键的分子内胺化

  摘要：

  据报道，有一种新的策略可以通过吡啶甲酰胺辅助的钯催化的C–H键活化反应从脂肪族胺中构建复杂的多环含氮杂环。该反应显示出广泛的底物范围，可用于合成各种氮杂双环支架，包括氮杂环丁烷和托烷类生物碱。该方法在天然存在的（-）-顺式-二甲基乙胺中的应用，这是前所未有的碳-碳键活化，其中涉及的电子对引发了环钯片段的分子内“ S N 2样”置换。第三中心，描述。

  DOI：

  10.1021/acs.orglett.7b02339

文献信息

• Iterative Arylation of Amino Acids and Aliphatic Amines via δ‐C(sp ³ )−H Activation: Experimental and Computational Exploration
  作者：Srimanta Guin、Pravas Dolui、Xinglong Zhang、Satyadip Paul、Vikas Kumar Singh、Sukumar Pradhan、Hediyala B. Chandrashekar、S. S. Anjana、Robert S. Paton、Debabrata Maiti

  DOI：10.1002/anie.201900479

  日期：2019.4.16

  mostly up to the γ‐position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote δ‐position by tuning the reactivity controlled by ligands. An organopalladium δ‐C(sp3)−H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction

  定向C H功能化已实现为传统方法的补充工具，可直接访问非蛋白原性氨基酸。尽管这样的过程主要限于γ位置。在当前的工作中，我们通过调节配体控制的反应性，证明了在远端δ位选择性地使氨基酸和类似的脂肪族胺具有多种（杂）芳基化作用。已分离出有机钯δ-C（sp 3）-H活化中间体，并进行了晶体学表征。实验研究与计算研究相结合进行的机理研究揭示了取决于基材结构的机理图上的差异。
• Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium Catalyzed Intramolecular Amination of C(sp³)–H and C(sp²)–H Bonds at γ and δ Positions
  作者：Gang He、Yingsheng Zhao、Shuyu Zhang、Chengxi Lu、Gong Chen

  DOI：10.1021/ja210660g

  日期：2012.1.11

  palladium-catalyzed intramolecular amination of C-H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C-H bond, especially the C(sp(3))-H bond of methyl groups, as functional

  已经开发出有效的方法来合成氮杂环丁烷、吡咯烷和二氢吲哚化合物，通过钯催化在吡啶酰胺 (PA) 保护的胺底物的 γ 和 δ 位置的 CH 键的分子内胺化。这些方法具有相对较低的催化剂负载量、使用廉价试剂和方便的操作条件。它们的选择性是可以预测的。这些方法强调使用未活化的 CH 键，尤其是甲基的 C(sp(3))-H 键，作为有机合成中的官能团。
• Radical C−H Alkylation with Ethers and Unactivated Cycloalkanes toward the Assembly of Tetrasubstituted Amino Acid Derivatives
  作者：Marcos San Segundo、Arkaitz Correa

  DOI：10.1002/adsc.202200716

  日期：2022.9.20

  A radical α−C−H alkylation of a collection of N-picolinamide amino acid derivatives with ethers and cycloalkanes as chemical feedstock is described. This cross-dehydrogenative coupling is distinguished by its reliable scalability and removable auxiliary group, and enables the assembly of a variety of tri- and tetrasubstituted amino acid compounds.

  描述了用醚和环烷烃作为化学原料的一组N-吡啶甲酰胺氨基酸衍生物的自由基 α-C-H 烷基化。这种交叉脱氢偶联以其可靠的可扩展性和可去除的辅助基团而著称，并且能够组装各种三取代和四取代的氨基酸化合物。
• Pd‐Catalyzed δ‐C(<i>sp</i>³)−H Thiolation of Amino Acid Derivatives
  作者：Andrés García‐Viada、Celia Sánchez‐González、Mario Martínez‐Mingo、Inés Alonso、Nuria Rodríguez、Juan C. Carretero

  DOI：10.1002/adsc.202300808

  日期：2023.11.21

  δ-thiolation of aliphatic α-amino acids catalyzed by a Pd(II)/Ag(I) system. This reaction employs disulfides as thiolating agents and N-COPy as directing group, providing valuable non-proteinogenic amino acid derivatives in moderate to good diastereoselectivities and yields. Remarkably, the method is also suitable for the late-stage functionalization of a dipeptide. Experimental and DFT studies have provided

  在此，我们报告了一种由 Pd(II)/Ag(I) 系统催化的脂肪族 α-氨基酸选择性 δ-硫醇化的方案。该反应使用二硫化物作为硫醇化剂，使用N -COPy作为导向基团，以中等至良好的非对映选择性和产率提供有价值的非蛋白氨基酸衍生物。值得注意的是，该方法也适用于二肽的后期功能化。实验和 DFT 研究为控制过程选择性和确定银盐的关键作用的机制和潜在因素提供了重要的见解。
• Polycyclic Azetidines and Pyrrolidines via Palladium-Catalyzed Intramolecular Amination of Unactivated C(sp3)–H Bonds
  作者：Jie Zhao、Xiao-Jing Zhao、Pei Cao、Ji-Kai Liu、Bin Wu

  DOI：10.1021/acs.orglett.7b02339

  日期：2017.9.15

  A novel strategy to construct complex polycyclic nitrogen-containing heterocycles from aliphatic amines via picolinamide-assisted palladium-catalyzed C–H bond activation reaction was reported. The reaction exhibits broad substrate scope for the synthesis of various azabicyclic scaffolds, including azetidines and tropane-class alkaloids. Application of this method to naturally occurring (−)-cis-myrtanylamine

  据报道，有一种新的策略可以通过吡啶甲酰胺辅助的钯催化的C–H键活化反应从脂肪族胺中构建复杂的多环含氮杂环。该反应显示出广泛的底物范围，可用于合成各种氮杂双环支架，包括氮杂环丁烷和托烷类生物碱。该方法在天然存在的（-）-顺式-二甲基乙胺中的应用，这是前所未有的碳-碳键活化，其中涉及的电子对引发了环钯片段的分子内“ S N 2样”置换。第三中心，描述。