ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | 188885-82-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate
• 英文别名: ethyl 4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate；ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate；ethyl (1SR,5RS,6SR)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate；ethyl (6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate；(1S*, 5R*, 6S*)-Ethyl 2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate
• CAS: 188885-82-7
• 化学式: C₉H₁₀O₃
• 分子量: 166.177
• InChiKey: TZVQBYHSMYCVGA-NJUXHZRNSA-N

物化性质

• 熔点：
  97-98 °C
• 沸点：
  262.4±19.0 °C(Predicted)
• 密度：
  1.264±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate 在 5percent Pd/C potassium hydrogen bifluoride 、 氢气 、 苄基三甲基氢氧化铵 作用下， 以 甲醇 、 乙醇 、 甲苯 为溶剂， 反应 2.5h， 生成 ethyl (1S, 3S, 5R, 6S)-3-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate
  参考文献：
  名称：

  2-氨基-3或6-氟双环[3.1.0]己烷-2,6-二羧酸衍生物作为强效，选择性和口服活性的II组代谢型谷氨酸受体激动剂的合成，SAR和药理学表征。

  摘要：

  高选择性和口服活性的II族代谢型谷氨酸受体激动剂（+）-2-氨基双环[3.1.0]己烷-2,6-二羧酸（4，LY354740），对该组的研究越来越感兴趣II mGluR。我们的兴趣集中在化合物4的构象约束形式上，因为似乎刚性形式不仅导致对II组mGluR的选择性而且具有口服活性。因此，我们基于分子的大小（与氢原子非常相似）和该原子的电负性（对分子中电子分布的影响）和碳-氟键能，将氟原子引入化合物4中。化合物（+）-7（MGS0008）是3-氟衍生物7-10中最好的化合物，保留了化合物4对mGluR2和mGluR3的激动活性（（+）-7：EC（50）= 29.4 +/- 3.3 nM和45.4 +/- 8。mGluR2和mGluR3分别为4 nM；4：mGluR2和mGluR3的EC（50）= 18.3 +/- 1.6 nM和62.8 +/- 12 nM），并提高了化合物4的口服活性（（+）-7：ED（50）=

  DOI：

  10.1021/jm000346k
• 作为产物：
  描述：

  ethyl (1S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolan]-3-ene-6-carboxylate 在 草酸 作用下， 以 二氯甲烷 为溶剂， 以80%的产率得到ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate
  参考文献：
  名称：

  Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)

  摘要：

  The asymmetric synthesis of(+)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY354740) 1, a potent and selective group 2 mGluR agonist, has been accomplished starting from the readily available enantiomerically pure cyclopentenone 4. Thus, cyclopropanation with ethyl(dimethylsulfuranylidene)acetate generated in situ with DBU, followed by deketalization gave rise to the dihydroxy bicyclic ketone 9. After protecting the ketone as 1,3-dioxolane and its transformation to the orthoformate 11, this was pyrolytically deoxygenated in a sealed tube to the bicyclic enone 13. The Synthesis was completed after hydrogenation, stereoselective Bucherer-Bergs reaction and hydantoin hydrolysis, yielding LY354740 (+)-1 with an e.e. greater than or equal to 98%. (C) 1997 Elsevier Science Ltd. rights reserved.

  DOI：

  10.1016/s0957-4166(97)00001-3

文献信息

• Desymmetrisation of Cyclopentadienylsilane by Asymmetric Cyclopropanation
  作者：Florent Allais、Rémy Angelaud、Boris Camuzat-Dedenis、Karine Julienne、Yannick Landais

  DOI：10.1002/ejoc.200390157

  日期：2003.3

  Desymmetrisation of silylcyclopenta-2,4-diene was carried out by an asymmetric copper(I)-mediated cyclopropanation. An in-depth investigation with various ligands led to the discovery that the PyBox ligands 10a−c were the most efficient ligands for this transformation and led to the cyclopropane 7a with an ee of up to 72%. Further studies aimed at providing insights into the origin of this enantiocontrol

  甲硅烷基环戊二烯-2,4-二烯的去对称化是通过不对称铜（I）介导的环丙烷化反应进行的。对各种配体的深入研究发现 PyBox 配体 10a-c 是这种转化最有效的配体，并导致环丙烷 7a 的 ee 高达 72%。还提供了旨在深入了解这种对映控制起源的进一步研究。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
• Intermediates and process for producing fluorine-containing amino acid compound by using the same
  申请人：Taisho Pharmaceutical Co., Ltd.

  公开号：US06392086B1

  公开（公告）日：2002-05-21

  The present inventions relate to a (1S,5R,6S)- or (1SR, 5RS, 6SR)-3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative represented by Formula (1): [in the formula, R represents OR1 or NR1R2, wherein R1 and R2 are identical or different, and each represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a (C3-C6 cycloalkyl) (C1-C6 alkyl) group, an aryl group, an aryl (C1-C6 alkyl) group, a (C1-C6 alkoxy) (C1-C6 alkyl) group, a C1-C6 hydroxyalkyl group, a (C1-C6 alkylthio) (C1-C6 alkyl) group, or a C1-C6 mercaptoalkyl group], and a process for producing the same, and a process for efficiently producing a fluorine-containing amino acid compound acting on group 2 metabotropic glutamate receptors, which has treatment effects or prevention effects on psychiatric diseases or neurological diseases, characterized by hydrogenating the derivative, and subsequently, subjecting it to hydantoination or aminocyanidation, followed by hydrolysis.

  本发明涉及一种由化学式（1）表示的（1S,5R,6S）-或（1SR, 5RS, 6SR）-3-氟-2-氧代双环［3.1.0］己-3-烯-6-羧酸衍生物：［在该式中，R代表OR1或NR1R2，其中R1和R2相同或不同，且每个代表氢原子、C1-C6烷基、C3-C6环烷基、（C3-C6环烷基）（C1-C6烷基）基团、芳基、芳基（C1-C6烷基）基团、（C1-C6烷氧基）（C1-C6烷基）基团、C1-C6羟基烷基、（C1-C6烷基硫基）（C1-C6烷基）基团或C1-C6巯基烷基］，以及用于生产该衍生物的方法，以及用于高效生产对第2组代谢型谷氨酸受体起作用的含氟氨基酸化合物的方法，该化合物具有治疗或预防精神疾病或神经疾病的效果，其特征在于氢化衍生物，随后经过咪唑醇化或氨基氰化，然后进行水解。
• The synthesis of isotopically labeled (+)-2-aminobicyclo[3.1.0]hexane-2,6-carboxylic acid and its 2-oxa- and 2-thia-analogs
  作者：William J. Wheeler、Douglas D. O'Bannon、Joseph H. Kennedy、James A. Monn、Roger W. Tharp-Taylor、Matthew J. Valli、Fengjiun Kuo

  DOI：10.1002/jlcr.956

  日期：2005.7

  As part of a program aimed at the design of conformationally constrained analogs of glutamic acid, (+)-2-aminobicyclo[3.1.0]hexane-2,6-carboxylic acid (1), identified as a highly potent, selective, group II metabotropic glutamate receptor agonist has been synthesized and studied clinically. Heterocyclic analogs of 1 were subsequently synthesized in which the C-2 methylene has been replaced by an oxygen atom (2) or a sulfur atom (3). C-14 labeled isotopomers of 1, 2 and 3 have been synthesized to facilitate pre-clinical ADME studies. A tritium labeled isotopomer of 1 was also synthesized for use in in vitro experiments. A stable labeled isotopomer of rac-1 was prepared for use as an internal standard for bioanalytical assays. The key step in each of these syntheses was the reaction of chiral ketone 4, 5 or 6 with K14CN/(NH4)2CO3 using the Bucherer–Berg protocol. In the preparation of the stable labeled isotopomer, rac-4-[13C2] was prepared in two steps from ethyl bromoacetate-[UL-13C2]; subsequent reaction of rac-4-[13C2] with K13CN/15NH4Cl/Na2CO3, followed by hydrolysis of the hydantoin yielded rac-1-[13C3,15N]. Copyright © 2005 John Wiley & Sons, Ltd.

  作为旨在设计构象限制型谷氨酸类似物的项目的一部分，合成并临床研究了(+)-2-氨基双环[3.1.0]己烷-2,6-羧酸（1），该化合物被确定为一种高度有效、选择性的二类代谢型谷氨酸受体激动剂。随后合成了1的杂环类似物，其中C-2亚甲基被氧原子（2）或硫原子（3）取代。合成了1、2和3的C-14标记同位素，以方便进行临床前的ADME研究。还合成了1的氚标记同位素，用于体外实验。为生物分析检测准备了稳定的标记同位素rac-1作为内标。这些合成中的关键步骤是手性酮4、5或6与K14CN/(NH4)2CO3的反应，采用Bucherer–Berg协议。在稳定标记同位素的制备中，rac-4-[13C2]是通过从乙基溴乙酸酯-[UL-13C2]的两步反应制得的；随后将rac-4-[13C2]与K13CN/15NH4Cl/Na2CO3反应，接着进行酰脲的水解，最终得到rac-1-[13C3,15N]。版权 © 2005 John Wiley & Sons, Ltd.
• [EN] PRODRUGS OF EXCITATORY AMINO ACIDS<br/>[FR] PROMEDICAMENTS D'ACIDES AMINES EXCITATEURS
  申请人：——

  公开号：WO2003104217A3

  公开（公告）日：2004-02-26
• Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures
  作者：James A. Monn、Lourdes Prieto、Lorena Taboada、Concepcion Pedregal、Junliang Hao、Matt R. Reinhard、Steven S. Henry、Paul J. Goldsmith、Christopher D. Beadle、Lesley Walton、Teresa Man、Helene Rudyk、Barry Clark、David Tupper、S. Richard Baker、Carlos Lamas、Carlos Montero、Alicia Marcos、Jaime Blanco、Mark Bures、David K. Clawson、Shane Atwell、Frances Lu、Jing Wang、Marijane Russell、Beverly A. Heinz、Xushan Wang、Joan H. Carter、Chuanxi Xiang、John T. Catlow、Steven Swanson、Helen Sanger、Lisa M. Broad、Michael P. Johnson、Kelly L. Knopp、Rosa M. A. Simmons、Bryan G. Johnson、David B. Shaw、David L. McKinzie

  DOI：10.1021/jm501612y

  日期：2015.2.26

  As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4(alpha)-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4 beta-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of proteinligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.