N-phenyl-hexahydro-4,7-epoxyisoindole-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: N-phenyl-hexahydro-4,7-epoxyisoindole-1,3-dione
• 英文别名: 2-phenyl-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione；N-phenyl-tetrahydro-4,7-epoxyisobenzopyrrole-1,3-dione；(4R,7S)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxyisoindole-1,3-dione
• 化学式: C₁₄H₁₁NO₃
• 分子量: 241.246
• InChiKey: PUHQMJSQZPUXJP-ZYANWLCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-phenyl-hexahydro-4,7-epoxyisoindole-1,3-dione 在 四氧化锇 、 N-甲基吗啉氧化物 作用下， 以 水 、 丙酮 、 叔丁醇 为溶剂， 反应 4.0h， 以90%的产率得到N-phenyl-5,6-dihydroxy-perhydro-4,7-epoxy-isoindole-1,3-dione
  参考文献：
  名称：

  UnyLinker二聚体杂质表征和工艺改进

  摘要：

  本文中，我们描述了UnyLinker二聚体的分离和表征，该二聚体如果不受控制，可以掺入寡核苷酸产物中。二聚体是由于异常的分子间ether催化的醚化作用而形成的。我们证明，通过简单地用NMO代替H 2 O 2作为助氧化剂，不会形成UnyLinker二聚体杂质。

  DOI：

  10.1016/j.tetlet.2017.01.101
• 作为产物：
  描述：

  呋喃 、 N-苯丁二醯亞胺 以 乙腈 为溶剂， 反应 5.0h， 以78%的产率得到N-phenyl-hexahydro-4,7-epoxyisoindole-1,3-dione
  参考文献：
  名称：

  UnyLinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach To Enhance the Purity of Drugs

  摘要：

  A novel universal linker (UnyLinker) molecule which has a conformationally rigid and chemically stable bridge head ring oxygen atom carrying a conventional 4,4'-dimethoxytrityl (DMT) and succinyl groups locked in a syn orientation has been developed to carry out oligonucleotide synthesis efficiently and smoothly. The geometry of the vicinal syn oxygen functionalized group allows fast and clean cleavage under standard aqueous ammonia deprotection conditions to afford high-quality oligonucleotides. No base modification is observed, based on the ion-pair UPLC-UV-MS (IP-HPLC-UV-MS) method with detection limit of <0.1%. A class of impurities formed by branching from the exocyclic amino group of nucleosides loaded onto a solid support has been eliminated by the use of this method. Examples demonstrating the versatile nature of this molecule are shown by syntheses of different chemistries such as 2'-deoxy, 2'-O-methyl, 2'-O-methoxyethyl, Lock nucleic acids (LNA), 2'-alpha-fluoro nucleic acids (FANA), conjugates such as 5'-phosphate monoester and biotin, and phosphate diester and phosphorothioate backbone modifications. This molecule was loaded onto several commercial solid supports and used in both gas-sparged and packed-bed automated DNA/RNA synthesizers. Large-scale syntheses (up to 700 mmol) of multiple phosphorothioate first- and second-generation antisense drugs on GE-Amersham's OligoProcess synthesizer are demonstrated further, showing that this chemistry could be used for efficient synthesis of multiple oligonucleotide drugs using a single raw material, thereby eliminating a difficult to characterize nucleoside-loaded polymer matrix used as a starting material. A mechanism for deprotection and cleavage of the linker molecule to liberate the free oligonucleotide is proposed. Characterization of the cyclic byproduct formed during release of the oligonucleotide is presented. The exo-syn configuration of the dihydroxy structure of the UnyLinker molecule is conclusively established by X-ray crystallography studies. A novel method to remove the last traces of osmium used during the synthesis of the UnyLinker molecule to reach undetectable levels (<1 ppm) is also described.

  DOI：

  10.1021/op8000178

文献信息

• Universal building blocks and support media for synthesis of oligonucleotides and their analogs
  申请人：——

  公开号：US20040152905A1

  公开（公告）日：2004-08-05

  Compounds for the synthesis of oligomeric compounds, particularly oligonucleotides and chemically modified oligonucleotide analogs, are provided. In addition, methods for functionalization of a support medium with a first monomeric subunit and methods for the synthesis of oligomeric compounds utilizing the novel compounds bound to support media are provided.

  提供用于合成寡聚化合物，特别是寡核苷酸和化学修饰的寡核苷酸类似物的化合物。此外，还提供了将支持介质功能化为第一单体亚基的方法，以及利用与支持介质结合的新化合物合成寡聚化合物的方法。
• Rhodium-Catalyzed Diastereoselective C–H Activation/[4 + 2] Annulation of α,β-Unsaturated Amides with Bicyclic Alkenes
  作者：Yan Wang、Sijia Shi、Wei Zhang、Yong Nian、Xiaowei Wu

  DOI：10.1021/acs.orglett.3c03819

  日期：2024.1.19

  rare example of rhodium-catalyzed C–H activation/[4 + 2] annulation of alkenyl amides with bicyclic alkenes under mild and green conditions. The reactivity of the rhodium catalyst in this study differed from that observed in cobalt-catalyzed C–H activation/[3 + 2] annulation between vinylic amides and bicyclic alkenes. In addition, the reaction was performed in EtOH at room temperature, which also displayed

  在此，我们报告了在温和和绿色条件下铑催化的烯基酰胺与双环烯烃的C-H活化/[4 + 2]环化的罕见例子。本研究中铑催化剂的反应性与钴催化乙烯基酰胺和双环烯烃之间的 C-H 活化/[3 + 2] 成环反应中观察到的反应性不同。此外，该反应在室温下在EtOH中进行，还表现出优异的非对映选择性、良好的官能团耐受性和空气相容性。以良好至优异的产率获得了一系列新型桥环骨架。使用 1 或 0.75 mol% 铑催化剂进行放大实验，以优异的产率提供了所需的桥环骨架。
• Convenient Large‐Scale Synthesis of Universal Solid Support
  作者：Vasulinga T. Ravikumar、R. Krishna Kumar、Xuefeng Zhu

  DOI：10.1080/00397910600639638

  日期：2006.8

  A simple, convenient large-scale synthesis of a universal solid support useful for the synthesis of oligonucleotides is described.
• UnyLinker dimer impurity characterization and process improvement
  作者：Joshua L. Brooks、Phil Olsen、Lijian Chen、Andrew A. Rodriguez

  DOI：10.1016/j.tetlet.2017.01.101

  日期：2017.3

  Herein, we describe the isolation and characterization of a UnyLinker dimer which, if left uncontrolled, can become incorporated in oligonucleotide products. The dimer is formed as a result of an unusual intermolecular osmium-catalyzed etherification. We demonstrate that by simply replacing H2O2 as the co-oxidant with NMO, none of the UnyLinker dimer impurity is formed.

  本文中，我们描述了UnyLinker二聚体的分离和表征，该二聚体如果不受控制，可以掺入寡核苷酸产物中。二聚体是由于异常的分子间ether催化的醚化作用而形成的。我们证明，通过简单地用NMO代替H 2 O 2作为助氧化剂，不会形成UnyLinker二聚体杂质。
• UnyLinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach To Enhance the Purity of Drugs
  作者：Vasulinga T. Ravikumar、R. Krishna Kumar、Phil Olsen、Max N. Moore、Recaldo L. Carty、Mark Andrade、Dennis Gorman、Xuefeng Zhu、Isaiah Cedillo、Zhiwei Wang、Lucio Mendez、Anthony N. Scozzari、Gerardo Aguirre、Ratnasamy Somanathan、Sylvain Berneès

  DOI：10.1021/op8000178

  日期：2008.5.1

  A novel universal linker (UnyLinker) molecule which has a conformationally rigid and chemically stable bridge head ring oxygen atom carrying a conventional 4,4'-dimethoxytrityl (DMT) and succinyl groups locked in a syn orientation has been developed to carry out oligonucleotide synthesis efficiently and smoothly. The geometry of the vicinal syn oxygen functionalized group allows fast and clean cleavage under standard aqueous ammonia deprotection conditions to afford high-quality oligonucleotides. No base modification is observed, based on the ion-pair UPLC-UV-MS (IP-HPLC-UV-MS) method with detection limit of <0.1%. A class of impurities formed by branching from the exocyclic amino group of nucleosides loaded onto a solid support has been eliminated by the use of this method. Examples demonstrating the versatile nature of this molecule are shown by syntheses of different chemistries such as 2'-deoxy, 2'-O-methyl, 2'-O-methoxyethyl, Lock nucleic acids (LNA), 2'-alpha-fluoro nucleic acids (FANA), conjugates such as 5'-phosphate monoester and biotin, and phosphate diester and phosphorothioate backbone modifications. This molecule was loaded onto several commercial solid supports and used in both gas-sparged and packed-bed automated DNA/RNA synthesizers. Large-scale syntheses (up to 700 mmol) of multiple phosphorothioate first- and second-generation antisense drugs on GE-Amersham's OligoProcess synthesizer are demonstrated further, showing that this chemistry could be used for efficient synthesis of multiple oligonucleotide drugs using a single raw material, thereby eliminating a difficult to characterize nucleoside-loaded polymer matrix used as a starting material. A mechanism for deprotection and cleavage of the linker molecule to liberate the free oligonucleotide is proposed. Characterization of the cyclic byproduct formed during release of the oligonucleotide is presented. The exo-syn configuration of the dihydroxy structure of the UnyLinker molecule is conclusively established by X-ray crystallography studies. A novel method to remove the last traces of osmium used during the synthesis of the UnyLinker molecule to reach undetectable levels (<1 ppm) is also described.