(3R,4S,8S,9R)-9-fluorocinchonane | 691382-02-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (3R,4S,8S,9R)-9-fluorocinchonane
• 英文别名: 9-deoxy-9-fluorocinchonidine；4-[(R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-fluoromethyl]quinoline
• CAS: 691382-02-2
• 化学式: C₁₉H₂₁FN₂
• 分子量: 296.388
• InChiKey: VTDMQMJPWPDMIW-KODHJQJWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  16.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3R,4S,8S,9R)-9-fluorocinchonane 在 盐酸 作用下， 以 甲醇 为溶剂， 以107 mg的产率得到(3R,4S,8S,9R)-9-fluorocinchonane dihydrochloride
  参考文献：
  名称：

  氟化奎宁生物碱：合成，X射线结构分析和抗疟原虫化学疗法

  摘要：

  在本文中，我们报告了通过直接亲核脱氧氟化作用合成一系列C9氟化的奎宁生物碱。这种转变产生了同时具有S和R构型的一氟亚甲基官能团的产品，这与类似S N 1的机理相一致。此外，奎宁环核的骨架重排产生了一系列环扩展的1-氮杂双环[3.2.2]壬烷系统。修饰的生物碱转化为相应的盐酸盐，并通过单晶X射线衍射分析进行表征。苄基氟原子采用薄纱的偏好在整个笼养化合物中始终观察到相对于质子化奎宁环氮原子的构象。相反，1-氮杂双环[3.2.2]壬烷体系的分子结构在氟原子和质子化叔胺之间建立了反关系。这构成在立体中心连位氟原子的定位在所述第一X射线证据抗到一个取代的铵阳离子。在体外评估了这些化合物对恶性疟原虫的NF54菌株（对所有已知的抗疟疾药物敏感）的药理功效。IC 50值低至267 n M被观察；这突出了这些材料在开发用于寄生虫化学治疗的新型药物方面的潜力。

  DOI：

  10.1002/chem.200900505
• 作为产物：
  描述：

  辛可尼丁 在 二乙胺基三氟化硫 作用下， 以 四氢呋喃 为溶剂， 反应 14.0h， 以11%的产率得到(3R,4S,8S,9R)-9-fluorocinchonane
  参考文献：
  名称：

  Deconstructing Quinine. Part 1. Toward an Understanding of the Remarkable Performance of Cinchona Alkaloids in Asymmetric Phase Transfer Catalysis

  摘要：

  A study of catalyst structure-activity/selectivity relationships for Cinchona alkaloid-based asymmetric phase transfer catalysis (APTC) is described. An array of substituent modifications at C(9) and the quinuclidine nitrogen were introduced to examine the role of steric and electronic effects on rate and selectivity. The synthesis of the catalysts began with manipulation of the C(9) hydroxyl group followed by alkylation of the quinuclidine nitrogen to generate the quaternary ammonium salt. Catalysts that contained large substituents attached to the quinuclidinium nitrogen were found to be the most selective and those in which the hydroxyl group was protected generally afforded faster catalysts. The presence of a polar group at C(9) significantly impacted catalyst activity.

  DOI：

  10.3987/com-10-s(e)108
• 作为试剂：
  描述：

  N-二苯亚甲基-甘氨酸叔丁酯 、 溴甲苯 在 (3R,4S,8S,9R)-9-fluorocinchonane 、 potassium hydroxide 作用下， 以 水 、 甲苯 为溶剂， 生成 t-butyl (R)-N-(diphenylmethylene)phenylalaninate 、 (S)-tert-butyl N-(diphenylmethylidene)phenylalanine
  参考文献：
  名称：

  Deconstructing Quinine. Part 1. Toward an Understanding of the Remarkable Performance of Cinchona Alkaloids in Asymmetric Phase Transfer Catalysis

  摘要：

  A study of catalyst structure-activity/selectivity relationships for Cinchona alkaloid-based asymmetric phase transfer catalysis (APTC) is described. An array of substituent modifications at C(9) and the quinuclidine nitrogen were introduced to examine the role of steric and electronic effects on rate and selectivity. The synthesis of the catalysts began with manipulation of the C(9) hydroxyl group followed by alkylation of the quinuclidine nitrogen to generate the quaternary ammonium salt. Catalysts that contained large substituents attached to the quinuclidinium nitrogen were found to be the most selective and those in which the hydroxyl group was protected generally afforded faster catalysts. The presence of a polar group at C(9) significantly impacted catalyst activity.

  DOI：

  10.3987/com-10-s(e)108

文献信息

• The First and Second <i>Cinchona</i> Rearrangement. Two Fundamental Transformations of Alkaloid Chemistry
  作者：M. Heiko Franz、Stefanie Röper、Rudolf Wartchow、H. M. R. Hoffmann

  DOI：10.1021/jo030363s

  日期：2004.4.1

  Stereochemistry, products, and driving forces of the “first and second Cinchona rearrangement” have been investigated and a unified theory is presented. The first cage expansion affords [3.2.2]azabicyclic α-amino ether and is formulated via a configurationally stable bridgehead iminium ion and quasiequatorial nucleophilic attack. The second cage expansion affords β-functionalized [3.2.2]azabicycles

  研究了“第一和第二次金鸡纳重排”的立体化学，产物和驱动力，并提出了统一的理论。第一次笼扩展提供了[3.2.2]氮杂双环α-氨基醚，并通过构型稳定的桥头亚胺离子和准四亲核攻击进行配制。第二个笼扩展提供了β-官能化的[3.2.2]氮杂双环。在这种情况下，假定存在非经典的氮桥阳离子，以说明保持构型和保持架扩展的潜在可逆性。第二种重新排列因所谓的肚带而受到青睐在三氟乙醇中的碱（6'-R = H）。在所有情况下，立体电子因素，C9处的电子需求，基态构型和溶剂类型都是至关重要的。描述了从9- nat前体制备9-表位构型的金鸡纳生物碱的两步方案。
• Fluorinated Quinine Alkaloids: Synthesis, X-ray Structure Analysis and Antimalarial Parasite Chemotherapy
  作者：Christoph Bucher、Christof Sparr、W. Bernd Schweizer、Ryan Gilmour

  DOI：10.1002/chem.200900505

  日期：2009.8.3

  gauche conformation relative to the protonated quinuclidine nitrogen atom was consistently observed throughout the cage‐conserved compounds. Conversely, the molecular architecture of the 1‐azabicyclo[3.2.2]nonane systems enforced an anti relationship between the fluorine atom and the protonated tertiary amine. This constitutes the first X‐ray evidence of a vicinal fluorine atom at a stereogenic centre

  在本文中，我们报告了通过直接亲核脱氧氟化作用合成一系列C9氟化的奎宁生物碱。这种转变产生了同时具有S和R构型的一氟亚甲基官能团的产品，这与类似S N 1的机理相一致。此外，奎宁环核的骨架重排产生了一系列环扩展的1-氮杂双环[3.2.2]壬烷系统。修饰的生物碱转化为相应的盐酸盐，并通过单晶X射线衍射分析进行表征。苄基氟原子采用薄纱的偏好在整个笼养化合物中始终观察到相对于质子化奎宁环氮原子的构象。相反，1-氮杂双环[3.2.2]壬烷体系的分子结构在氟原子和质子化叔胺之间建立了反关系。这构成在立体中心连位氟原子的定位在所述第一X射线证据抗到一个取代的铵阳离子。在体外评估了这些化合物对恶性疟原虫的NF54菌株（对所有已知的抗疟疾药物敏感）的药理功效。IC 50值低至267 n M被观察；这突出了这些材料在开发用于寄生虫化学治疗的新型药物方面的潜力。
• Deconstructing Quinine. Part 1. Toward an Understanding of the Remarkable Performance of Cinchona Alkaloids in Asymmetric Phase Transfer Catalysis
  作者：Scott E. Denmark

  DOI：10.3987/com-10-s(e)108

  日期：——

  A study of catalyst structure-activity/selectivity relationships for Cinchona alkaloid-based asymmetric phase transfer catalysis (APTC) is described. An array of substituent modifications at C(9) and the quinuclidine nitrogen were introduced to examine the role of steric and electronic effects on rate and selectivity. The synthesis of the catalysts began with manipulation of the C(9) hydroxyl group followed by alkylation of the quinuclidine nitrogen to generate the quaternary ammonium salt. Catalysts that contained large substituents attached to the quinuclidinium nitrogen were found to be the most selective and those in which the hydroxyl group was protected generally afforded faster catalysts. The presence of a polar group at C(9) significantly impacted catalyst activity.