(2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(diethoxyphosphoryl)(difluoro)methyl]phenyl}propanoic acid | 150618-05-6

• 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)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(diethoxyphosphoryl)(difluoro)methyl]phenyl}propanoic acid
• 英文别名: L-N-Boc-F2Pmp(OEt)2-OH；N-Boc diethyl 4-phosphono(difluoromethyl)-L-phenylalanine；(2S)-3-[4-[diethoxyphosphoryl(difluoro)methyl]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 150618-05-6
• 化学式: C₁₉H₂₈F₂NO₇P
• 分子量: 451.404
• InChiKey: CYIRYOABMSXHDK-HNNXBMFYSA-N

物化性质

• 沸点：
  560.4±50.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  30
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(diethoxyphosphoryl)(difluoro)methyl]phenyl}propanoic acid 在 potassium carbonate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Development of caged non-hydrolyzable phosphoamino acids and application to photo-control of binding affinity of phosphopeptide mimetic to phosphopeptide-recognizing protein

  摘要：

  The design and synthesis of caged non-hydrolyzable phospho-serine, -threonine, and -tyrosine derivatives that generate parent non-hydrolyzable phosphoamino acids, containing a difluoromethylene unit instead of the oxygen of a phosphoester, after UV-irradiation are described. The caged non-hydrolyzable amino acids were incorporated into peptides by standard Fmoc solid-phase peptide synthesis, and the obtained peptides were successfully converted to the parent non-hydrolyzable phosphopeptides by UV-irradiation. Application of the caged non-hydrolyzable phosphoserine-containing peptide to photo-control the binding affinity of the peptide to 14-3-3 beta protein is also reported. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.04.002
• 作为产物：
  描述：

  溴氟甲基膦酸二乙酯 在 palladium on activated charcoal 甲醇 、 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 jones reagent 、 Lipase PS 、 偶氮二异丁腈 、 二苯基膦叠氮化物 、 氢气 、 sodium hydride 、 potassium carbonate 、 三乙胺 、 copper(I) bromide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 N,N-二甲基乙酰胺 、 乙酸乙酯 、 丙酮 、 苯 为溶剂， 20.0~90.0 ℃ 、101.33 kPa 条件下， 反应 49.5h， 生成 (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(diethoxyphosphoryl)(difluoro)methyl]phenyl}propanoic acid
  参考文献：
  名称：

  Enzymatic desymmetrization of prochiral 2-benzyl-1,3-propanediol derivatives: A practical chemoenzymatic synthesis of novel phosphorylated tyrosine analogues

  摘要：

  (Phosphonomethyl)phenylalanine (Pmp) and (phosphonodifluoromethyl)phenylalanine (F(2)Pmp) as well as their beta-amino acid congeners were prepared as a protecting variant amenable to the peptide synthesis from readily available 2-benzyl-1,3-propandiols possessing either a diethylphosphonomethyl- or diethylphosphonodifluoromethyl functionality at the para-position via the lipase-catalyzed desymmetrization. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(98)00586-9

文献信息

• Stereoselective Synthesis of CF₂-Substituted Phosphothreonine Mimetics and Their Incorporation into Peptides Using Newly Developed Deprotection Procedures^,
  作者：Akira Otaka、Etsuko Mitsuyama、Takayoshi Kinoshita、Hirokazu Tamamura、Nobutaka Fujii

  DOI：10.1021/jo000169v

  日期：2000.8.1

  combination of a first-step reagent [0.3 M BSTFA-TBAI in CH(2)Cl(2), BF(3).Et(2)O] followed by a second-step reagent [1 M TMSOTf-thioanisole in TFA, m-cresol, EDT] was developed for use in solid-phase protocols. A 12-residue Cdc (cell division cycle) 2-peptide 41, possessing two nonhydrolyzable phosphoamino acid mimetics (F(2)Pmab 6 and F(2)Pmp 4), was subjected to this deprotection procedure and was obtained

  本文描述了CF（2）取代的不可水解磷苏氨酸衍生物（33、39及其对映异构体）的所有四个立体异构体的立体选择性合成及其在肽中的结合。合成这些氨基酸的关键是模拟二级磷酸酯模拟二氟甲基膦酸酯单元以及两个立体中心的生成。前者使用BrZnCF（2）P（O）（OEt）（2）（8）和β-碘-α，β-不饱和酯12的Cu（I）介导的交叉偶联反应实现，立体化学为α-和β-立体中心都是使用硼烷-10,2-舒马坦作为手性助剂建立的。手性α，β-不饱和酰基磺酰胺的非对映选择性氢化（对于β中心）（例如，使用图16a）和随后的立体选择性溴化（对于苏糖衍生物的α中心）或胺化（对于赤型（allo）衍生物的α中心）。溴化物酯交换成苄基酯，然后叠氮化物置换卤素，然后还原生成的叠氮化物，然后进行Boc保护，最后除去苄基，同时提供L-和D-磷酸苏氨酸的模拟物（39及其对映体）。另一方面，通过上述胺化产物的酯交换反应，然后氢解除去苄
• Preparation of L-(Phosphonodifluoromethyl)phenylalanine derivatives as non-hydrolyzable mimetics of O-phosphotyrosine
  作者：Jay Wrobel、Arlene Dietrich

  DOI：10.1016/s0040-4039(00)73631-8

  日期：1993.5

  N-t-BOC-L-(Phosphonodifluoromethyl)phenylalanine benzyl ester (1) was prepared in 5 steps from N-t-BOC-L-tyrosine benzyl eser O-triflate (4). Compound 1 was further converted to derivatives 2 and 3 which are potentially suitable for peptide synthesis. Analogs 1 - 3 are non-hydrolyzable mimetics of O-phosphotyrosine.

  Nt-BOC-L-（膦二氟甲基）苯丙氨酸苄酯（1）由Nt-BOC-L-酪氨酸苄基酯O-三氟甲磺酸酯（4）分5步制备。将化合物1进一步转化为可能适合于肽合成的衍生物2和3。类似物1-3是O-磷酸酪氨酸的不可水解模拟物。
• Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T‐Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy
  作者：Jiajun Dong、Jinmin Miao、Yiming Miao、Zihan Qu、Sheng Zhang、Peipei Zhu、Florian Wiede、Brenson A. Jassim、Yunpeng Bai、Quyen Nguyen、Jianping Lin、Lan Chen、Tony Tiganis、W. Andy Tao、Zhong-Yin Zhang

  DOI：10.1002/anie.202303818

  日期：——

  An inhibitor for protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) was discovered and transformed into a first-in-class, potent, and selective dual PROTAC degrader for both targets. The degrader promotes antigen presentation of tumor cells and activates CD8+ T-cells. Importantly, the degrader is effective in vivo and suppresses syngeneic tumor growth.

  发现了蛋白酪氨酸磷酸酶 1B (PTP1B) 和 T 细胞蛋白酪氨酸磷酸酶 (TC-PTP) 抑制剂，并将其转化为针对这两个靶标的一流、有效、选择性的双 PROTAC 降解剂。该降解剂促进肿瘤细胞的抗原呈递并激活 CD8+ T 细胞。重要的是，该降解剂在体内有效并抑制同基因肿瘤生长。
• Discovery of a selective TC-PTP degrader for cancer immunotherapy
  作者：Jinmin Miao、Jiajun Dong、Yiming Miao、Yunpeng Bai、Zihan Qu、Brenson A. Jassim、Bo Huang、Quyen Nguyen、Yuan Ma、Allison A. Murray、Jinyue Li、Philip S. Low、Zhong-Yin Zhang

  DOI：10.1039/d3sc04541b

  日期：——

  We report the first, potent and selective PROTAC degrader for TC-PTP. The degrader enhances TC-PTP substrates’ phosphorylation levels, promotes antigen presentation in tumor, and enhances T-cell activation and CAR-T cell efficiency.

  我们报告了首个强效且具有选择性的 TC-PTP PROTAC 降解剂。这种降解剂能提高 TC-PTP 底物的磷酸化水平，促进肿瘤中的抗原呈递，并增强 T 细胞活化和 CAR-T 细胞的效率。
• Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands
  作者：Zhu-Jun Yao、C. Richter King、Tin Cao、James Kelley、George W. A. Milne、Johannes H. Voigt、Terrence R. Burke

  DOI：10.1021/jm980388x

  日期：1999.1.1

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.