(1R,2S)-N,N-diethyl-2-[(1R)-1-hydroxypropyl]-1-phenylcyclopropane-1-carboxamide | 172016-09-0

• 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: (1R,2S)-N,N-diethyl-2-[(1R)-1-hydroxypropyl]-1-phenylcyclopropane-1-carboxamide
• CAS: 172016-09-0
• 化学式: C₁₇H₂₅NO₂
• 分子量: 275.391
• InChiKey: FGVGMSHUHNZLHB-INMHGKMJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1R,2S)-N,N-diethyl-2-[(1R)-1-hydroxypropyl]-1-phenylcyclopropane-1-carboxamide 在 重铬酸吡啶 、 4 A molecular sieve 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 (1R,2S)-N,N-diethyl-2-[(1S)-1-hydroxypropyl]-1-phenylcyclopropane-1-carboxamide
  参考文献：
  名称：

  Conformational Restriction by Repulsion between Adjacent Substituents on a Cyclopropane Ring:  Design and Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as Potent NMDA Receptor Antagonists

  摘要：

  Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereo selectively, the facial selectivity was reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-a and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.

  DOI：

  10.1021/jo9518056
• 作为产物：
  描述：

  2-(Hydroxymethyl)-1-phenylcyclopropanecarbonitrile 在 氢氧化钾 、 正丁基锂 、 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 22.0h， 生成 (1R,2S)-N,N-diethyl-2-[(1R)-1-hydroxypropyl]-1-phenylcyclopropane-1-carboxamide
  参考文献：
  名称：

  Conformational Restriction by Repulsion between Adjacent Substituents on a Cyclopropane Ring:  Design and Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as Potent NMDA Receptor Antagonists

  摘要：

  Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereo selectively, the facial selectivity was reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-a and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.

  DOI：

  10.1021/jo9518056

文献信息

• Highly stereoselective nucleophilic addition to cyclopropyl carbonyls: The facial selectivity in the cyclopropyl ketones is opposite to that in the corresponding aldehyde
  作者：Shizuka Ono、Satoshi Shuto、Akira Matsuda

  DOI：10.1016/0040-4039(95)02133-7

  日期：1996.1

  Nucleophilic addition reaction of Grignard reagents to cyclopropylcarbaldehyde 4 proceeded highly selectively from the si-face to afford 5 in high yield. Although hydride reduction of the corresponding ketone 7 with L-Selectride® also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-face addition product 5. On the other hand, reduction of 7 with DIBAL-H afforded

  格氏试剂的亲核加成反应来cyclopropylcarbaldehyde 4从进行高度选择性SI面取向，得到5以高收率。虽然相应的酮的氢化物还原7与三仲丁基硼氢化锂®也进行高度非对映选择性，面部选择性被逆转，得到重-面加成产物5。另一方面，用DIBAL-H还原7得到高产率的硅表面加成产物6。结果表明，这些亲核加成反应是通过两等分的s-进行的。反式或小号-顺式环丙烷衍生物的构象。