(+/-)-cis-2-fluoro-2-phenylcyclopropanecarboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (+/-)-cis-2-fluoro-2-phenylcyclopropanecarboxylic acid
• 英文别名: rel-(1R,2R)-2-fluoro-2-phenylcyclopropane-1-carboxylic acid；(1R,2R)-2-fluoro-2-phenylcyclopropane-1-carboxylic acid
• 化学式: C₁₀H₉FO₂
• 分子量: 180.179
• InChiKey: ULOVTWLQHAOUKT-SCZZXKLOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (+/-)-cis-2-fluoro-2-phenylcyclopropanecarboxylic acid 在 4-二甲氨基吡啶 、 二苯基膦叠氮化物 、 乙酸酐 、 溶剂黄146 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 环己烷 、 叔丁醇 为溶剂， 反应 68.0h， 生成 ((1S,2S)-2-fluoro-2-phenyl-cyclopropyl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Fluorinated Phenylcyclopropylamines. 2. Effects of Aromatic Ring Substitution and of Absolute Configuration on Inhibition of Microbial Tyramine Oxidase

  摘要：

  A series of para-substituted diastereopure cis- and trans-2-fluoro-2-arylcyclopropylamines were synthesized and these were investigated as inhibitors of microbial tyramine oxidase from Arthrobacter sp. All compounds were shown to be competitive inhibitors of this enzyme. The nature of the para-substituents in the more potent trans-isomer (cis-relationship between fluorine and the amino group) of 2-fluoro-2-arylcyclopropylamine influenced the inhibitory potency in a consistent fashion. Thus, electron-withdrawing groups (F, Cl) slightly decreased the activity, while the methyl group (+ I substituent) increased the activity by a factor of ca. 7 compared to trans-2-fluoro-2-phenylcyclopropylamine and by a factor of 90 compared to tranylcypromine. Activity also was strongly dependent on the absolute configuration. The (1S,2S)-enantiomer of 2-fluoro-2-phenylcyclopropylamine was an excellent inhibitor of tyramine oxidase whereas the (1R,2R)-enantiomer was essentially devoid of activity.

  DOI：

  10.1021/jm049957t
• 作为产物：
  描述：

  1-氟乙烯基苯 在 copper acetylacetonate 磷脂酶B 作用下， 以 phosphate buffer 、 二氯甲烷 为溶剂， 反应 175.0h， 生成 (+/-)-cis-2-fluoro-2-phenylcyclopropanecarboxylic acid
  参考文献：
  名称：

  Asymmetric Cyclopropanation of Vinyl Fluorides: Access to Enantiopure Monofluorinated Cyclopropane Carboxylates

  摘要：

  过渡金属催化的环丙烷化反应，通过与烷基二氮酸酯的反应，能够平稳地获得由烃基醇或芳香族乙烯氟化物（由相应烯烃经过溴氟化和后续去溴化反应制得）的外消旋1 : 1混合物的顺/反凉氟化环丙烷羧酸酯。采用手性纯双（噁唑啉）配体和铜（I）三氟甲磺酸盐使得该反应具备顺式立体选择性和对映选择性。例如，α-氟苯乙烯（3a）与叔丁基二氮酸酯在以(S)-叔亮氨酸为基础的催化剂11b和CuOTf的存在下反应，得到4 : 1的反-2-氟-2-苯基环丙烷羧酸酯（4e），其对映体过量率（ee）为93%，以及相应的顺式异构体5e，其对映体过量率为89%。反式异构体4e的绝对构型已经通过衍生物的X射线结构分析确定为（1S，2S）。

  DOI：

  10.1055/s-2000-7103

文献信息

• Synthesis, reactions and structural features of monofluorinated cyclopropanecarboxylates
  作者：Günter Haufe、Thomas C. Rosen、Oliver G.J. Meyer、R. Fröhlich、Kari Rissanen

  DOI：10.1016/s0022-1139(02)00040-4

  日期：2002.4

  Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of vinylfluorides with diazoacetates. From α-fluorostyrene and tert-butyl diazoacetate in the presence of 2 mol% of an enantiopure bis(oxazoline) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high

  通过氟乙烯与重氮乙酸酯的过渡金属催化反应，可以得到外消旋或旋光形式的单氟化环丙烷羧酸酯。从α氟苯乙烯和叔丁基重氮乙酸酯在2摩尔％的对映纯的双恶唑啉铜配合物存在下，的81:19混合物叔丁基反式-和顺用获得-2-氟-2- phenylcyclopropanecarboxylates对映体过量（ee）分别为93％或89％。相应的外消旋乙酯被用作合成顺式和反式羧酰胺的原料-抗抑郁药反式环丙胺类似物的异构体及其几种氟化的环丙基甲基和环丙基乙基胺。还合成了相应的对映体纯的环丙基甲醇及其一些衍生物。通过X射线晶体学检查选择了这些化合物的固态结构。特别是，顺式构型的氟化苯基环丙烷衍生物显示出非常紧密的分子间CH⋯FC接触。在（1S，2R）-（2-氟-2-苯基环丙基）甲醇的N-（4-溴苯基）氨基甲酸酯中发现了最短的这种距离（2.17A）。
• Fluorinated Phenylcyclopropylamines. 1. Synthesis and Effect of Fluorine Substitution at the Cyclopropane Ring on Inhibition of Microbial Tyramine Oxidase
  作者：Shinichi Yoshida、Oliver G. J. Meyer、Thomas C. Rosen、Günter Haufe、Song Ye、Milton J. Sloan、Kenneth L. Kirk

  DOI：10.1021/jm030398k

  日期：2004.3.1

  s and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition

  为了研究效果，合成了两个非对映体纯的苯基环丙胺类似物2-氟-2-苯基环丙胺和2-氟-2-苯基环丙基烷基胺，以及2-氟-1-苯基环丙胺和2-氟-1-苯基环丙基甲胺。取代对单胺氧化酶抑制的影响 使用可商购的微生物酪胺氧化酶测定抑制活性。在抑制实验之前进行酪胺氧化酶的表征，证实了较早的建议，即该酶是对氨基脲敏感的含铜单胺氧化酶。最有效的竞争性抑制剂是反式-2-氟-2-苯基环丙胺，其IC（50）值比非氟化化合物tranylcypromine低10倍。发现2-氟-1-苯基环丙基甲基胺是酪胺氧化酶的弱非竞争性抑制剂。直接与环丙烷环键合的游离氨基和与氨基成顺式关系的氟原子的存在是增加酪氨酸氧化酶抑制作用的结构特征。
• New indications for the potential involvement of C–F-bonds in hydrogen bonding
  作者：Roland Fröhlich、Thomas C. Rosen、Oliver G.J. Meyer、Kari Rissanen、Günter Haufe

  DOI：10.1016/j.molstruc.2005.10.033

  日期：2006.4

  Solid state structures of a selection of 2-fluoro-2-phenylcyclopropane derivatives were examined by X-ray crystallography in order to identify short intermolecular contacts of C-F groups to H-X moieties (X = C, N). Particularly, several cis-configured fluorinated phenylcyclopropane derivatives showed extremely close intermolecular contacts. The shortest of such C-(HF)-F-...-C-distances (2.17 angstrom, C-F-H angle 162 degrees) was found in (IS,2R)-(2-fluoro-2-phenylcyclopropyl)methyl N-(4-bromophenyl)carbamate (8) and the closest N-(HF)-F-...-C-interaction (2.01 angstrom, C-F-H angle 167 degrees) was found in (+/-)-cis-2-fluoro-2-phenylcyclopropyl carboxamide (4). Comparison of the structures of several of the fluorinated cyclopropares with those of the non-fluorinated counterparts revealed that close intermolecular contacts of fluorine substituents to hydrogen atoms are not solely due to crystal packing effects, but are also caused by weak X-H... F-C hydrogen bridges. (c) 2005 Elsevier B.V. All rights reserved.
• Asymmetric Cyclopropanation of Vinyl Fluorides: Access to Enantiopure Monofluorinated Cyclopropane Carboxylates
  作者：Oliver G. J. Meyer、Roland Fröhlich、Günter Haufe

  DOI：10.1055/s-2000-7103

  日期：——

  The transition metal catalyzed cyclopropanation with alkyl diazoacetates of aliphatic or aromatic vinyl fluorides, prepared from the corresponding alkenes by bromofluorination and subsequent dehydrobromination, provides a smooth access to racemic 1 : 1 mixtures of cis/trans isomeric monofluorinated cyclopropane carboxylates. The application of enantiopure bis(oxazoline) ligands and copper(I) triflate makes the reaction trans-diastereoselective and enantioselective. For example, treatment of α-fluorostyrene (3a) with tert-butyl diazoacetate in the presence of 2 mol% of the catalyst prepared from (S)-tert-leucine-based 11b and CuOTf gave a 4 : 1 mixture of trans-2-fluoro-2-phenylcyclopropanecarboxylate (4e) with 93% ee and the corresponding cis-isomer 5e with 89% ee. The absolute configuration of the trans-isomer 4e has been determined to be (1S,2S) by X-ray structure analysis of a derivative.

  过渡金属催化的环丙烷化反应，通过与烷基二氮酸酯的反应，能够平稳地获得由烃基醇或芳香族乙烯氟化物（由相应烯烃经过溴氟化和后续去溴化反应制得）的外消旋1 : 1混合物的顺/反凉氟化环丙烷羧酸酯。采用手性纯双（噁唑啉）配体和铜（I）三氟甲磺酸盐使得该反应具备顺式立体选择性和对映选择性。例如，α-氟苯乙烯（3a）与叔丁基二氮酸酯在以(S)-叔亮氨酸为基础的催化剂11b和CuOTf的存在下反应，得到4 : 1的反-2-氟-2-苯基环丙烷羧酸酯（4e），其对映体过量率（ee）为93%，以及相应的顺式异构体5e，其对映体过量率为89%。反式异构体4e的绝对构型已经通过衍生物的X射线结构分析确定为（1S，2S）。
• Fluorinated Phenylcyclopropylamines. 2. Effects of Aromatic Ring Substitution and of Absolute Configuration on Inhibition of Microbial Tyramine Oxidase
  作者：Thomas C. Rosen、Shinichi Yoshida、Roland Fröhlich、Kenneth L. Kirk、Günter Haufe

  DOI：10.1021/jm049957t

  日期：2004.11.1

  A series of para-substituted diastereopure cis- and trans-2-fluoro-2-arylcyclopropylamines were synthesized and these were investigated as inhibitors of microbial tyramine oxidase from Arthrobacter sp. All compounds were shown to be competitive inhibitors of this enzyme. The nature of the para-substituents in the more potent trans-isomer (cis-relationship between fluorine and the amino group) of 2-fluoro-2-arylcyclopropylamine influenced the inhibitory potency in a consistent fashion. Thus, electron-withdrawing groups (F, Cl) slightly decreased the activity, while the methyl group (+ I substituent) increased the activity by a factor of ca. 7 compared to trans-2-fluoro-2-phenylcyclopropylamine and by a factor of 90 compared to tranylcypromine. Activity also was strongly dependent on the absolute configuration. The (1S,2S)-enantiomer of 2-fluoro-2-phenylcyclopropylamine was an excellent inhibitor of tyramine oxidase whereas the (1R,2R)-enantiomer was essentially devoid of activity.