ethyl (S)-2,2-difluoro-3-(((R)-2-methoxy-1-phenylethyl)amino)-4-methylpentanoate | 676460-36-9

• 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: ethyl (S)-2,2-difluoro-3-(((R)-2-methoxy-1-phenylethyl)amino)-4-methylpentanoate
• 英文别名: ethyl (3S)-2,2-difluoro-3-[[(1R)-2-methoxy-1-phenylethyl]amino]-4-methylpentanoate
• CAS: 676460-36-9
• 化学式: C₁₇H₂₅F₂NO₃
• 分子量: 329.387
• InChiKey: JBFWTRPHGJDNFB-GJZGRUSLSA-N

物化性质

• 沸点：
  378.6±42.0 °C(Predicted)
• 密度：
  1.090±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  23
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (S)-2,2-difluoro-3-(((R)-2-methoxy-1-phenylethyl)amino)-4-methylpentanoate 在 copper(l) iodide 、 methyllithium lithium bromide 、 palladium 10% on activated carbon 、 双氧水 、 二异丁基氢化铝 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium chloride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 、 乙硫醇 为溶剂， 反应 17.5h， 生成 methyl-((2R,5S,Z)-2-benzyl-5-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanamido)-4-fluoro-6-methylhept-3-enoyl) L-prolyl-L-tryptophanate
  参考文献：
  名称：

  二肽基肽酶 III (DPP3) 的高效氟乙烯拟肽抑制剂的设计与合成

  摘要：

  二肽基肽酶 III (DPP3) 是一种普遍表达的锌依赖性肽切割酶，可选择性水解酰胺键以将N端二肽片段从生理上重要的寡肽上切割下来。DPP3 被发现存在于多种不同类型的细胞中，并且似乎参与了各种生理过程（例如伤害感受、血压控制、蛋白质转换）。以缓慢转化的肽底物酪啡肽 (VVYPW) 为起点，我们用氟乙烯生物等排体取代易裂键来设计基态抑制剂，这导致了迄今为止最有效的基于肽的 DPP3 抑制剂。

  DOI：

  10.1016/j.bmc.2022.116831
• 作为产物：
  描述：

  (R)-(-)-2-甲氧基-1-苯乙胺 在 RhCl(PPh₃)3 diethylzinc 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 4.5h， 生成 ethyl (S)-2,2-difluoro-3-(((R)-2-methoxy-1-phenylethyl)amino)-4-methylpentanoate
  参考文献：
  名称：

  SmI₂-Mediated Reduction of γ,γ-Difluoro-α,β-enoates with Application to the Synthesis of Functionalized (Z)-Fluoroalkene-Type Dipeptide Isosteres

  摘要：

  A samarium diiodide (SmI2)-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates (15, 29, and 34) was successfully applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres (23, 30, and 35), which have served as potential dipeptide mimetics. Reduction of the gamma,gamma-difluoro-alpha,beta-enoates by SmI2 proceeded via successive two-electron transfers to form dienolate species which upon kinetically controlled trapping with t-BuOH yielded Xaa-Gly-type fluoroalkene isosteres exemplified by 23, 30, and 35. Replacement of the t-BuOH kinetic trapping agent with aldehydes or ketones provided access to a-substituted fluoroalkene isosteres (43 and 45) through aldol reactions of Sm-dienolates with the carbonyl compounds. Of particular note, the use of the SmI2-HCHO reagent system with chiral enoate 34 provided D-Phe-psi[(Z)-CF=CH]-D/L-Ser isosteres (45), which could be converted to enantiomerically pure isosteres (49-52) that bore a variety of side chain functionalities at the a-position. This was achieved by a sequence of manipulations consisting of beta-lactone formation followed by chromatographic separation and ring-opening with soft nucleophiles. Included in the present work is the first utilization of a Rh-catalyzed Reformatsky reaction of chiral imines for the stereoselective preparation of alpha,alpha-difluoro-beta-amino acid derivatives (28 and 33). The appropriate choice of reagents (carbonyl compounds for kinetic trapping or ring-opening nucleophiles and imines for Reformatsky reactions) allows the presented methodology to yield various fluoroalkene isosteres possessing a wide range of side chain functionalities.

  DOI：

  10.1021/jo035709d

文献信息

• Diastereoselective synthesis of highly functionalized fluoroalkene dipeptide isosteres and its application to Fmoc-based solid-phase synthesis of a cyclic pentapeptide mimetic
  作者：Tetsuo Narumi、Kenji Tomita、Eriko Inokuchi、Kazuya Kobayashi、Shinya Oishi、Hiroaki Ohno、Nobutaka Fujii

  DOI：10.1016/j.tet.2008.02.076

  日期：2008.5

  A diastereoselective and divergent method for synthesis of a highly functionalized (Z)-fluoroalkene dipeptide isosteres has been developed. The key feature of this synthetic method is an efficient one-pot reaction involving reduction/asymmetric alkylation via transmetalation, which produces trans-amide type (Z)-fluoroalkenes flanking two stereogenic centers in high yields, with excellent (Z)-selectivity

  已经开发了用于合成高度官能化的（Z）-氟代烯烃二肽等排体的非对映选择性和发散方法。该合成方法的关键特征是有效的一锅反应，涉及通过金属转移进行的还原/不对称烷基化反应，该反应可高产率地产生侧接两个立构中心的反酰胺型（Z）-氟代烯烃，并具有出色的（Z）选择性和非对映选择性。还描述了实用的基于Fmoc的固相合成特定的CXCR4拮抗假肽25，该肽含有（Z）-氟烯烃等排异构体。
• Monofluoroalkene‐Isostere as a ¹⁹ F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane‐Bound PGLa and (KIGAKI) ₃
  作者：Myriam Drouin、Parvesh Wadhwani、Stephan L. Grage、Jochen Bürck、Johannes Reichert、Sébastien Tremblay、Marie Sabine Mayer、Christian Diel、Alexander Staub、Jean‐François Paquin、Anne S. Ulrich

  DOI：10.1002/chem.201905054

  日期：2020.2.3

  Solid-state 19 F NMR is a powerful method to study the interactions of biologically active peptides with membranes. So far, in labelled peptides, the 19 F-reporter group has always been installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non-hydrolyzable peptide bond mimics, we have synthesized a monofluoroalkene-based dipeptide isostere, Val-Ψ[(Z)-CF=CH]-Gly, and

  固态19 F NMR是研究生物活性肽与膜相互作用的有力方法。到目前为止，在标记的肽中，19 F-报告基团一直被安装在氨基酸的侧链上。考虑到单氟烯烃是不可水解的肽键模拟物，我们合成了基于单氟烯烃的二肽等位物Val-Ψ[（Z）-CF = CH] -Gly，并将其插入到两个经过充分研究的抗菌素序列中肽：PGLa和（KIGAKI）3是α-螺旋和β-折叠的代表。研究了这些标记肽的构象和生物学活性，以评估一氟烯烃对19 F NMR结构分析的适用性。