endo-7-<3-(cyclopentyloxy)-4-methoxyphenyl>hexahydropyrrolizidin-3-one

• 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: endo-7-<3-(cyclopentyloxy)-4-methoxyphenyl>hexahydropyrrolizidin-3-one
• 英文别名: (7RS,7aRS)-7-[3-(cyclopentyloxy)-4-(methyloxy)phenyl]hexahydro-3H-pyrrolizin-3-one；(7SR,7aSR)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one；rac-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one；(7R,8R)-7-(3-cyclopentyloxy-4-methoxyphenyl)-1,2,5,6,7,8-hexahydropyrrolizin-3-one
• 化学式: C₁₉H₂₅NO₃
• 分子量: 315.412
• InChiKey: PENUWCJNZWDLCW-HZPDHXFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-环戊氧-4-甲氧基苯甲醛 在 三甲基溴硅烷 、 ammonium acetate 、 水 、 氢气 、 四氯化锡 、 sodium hydride 、 sodium cyanoborohydride 、 溶剂黄146 、 三乙胺 、 sodium bromide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 乙腈 、 mineral oil 为溶剂， -90.0~60.0 ℃ 、4.0 MPa 条件下， 反应 55.35h， 生成 endo-7-<3-(cyclopentyloxy)-4-methoxyphenyl>hexahydropyrrolizidin-3-one
  参考文献：
  名称：

  PDE IVb抑制剂的合成。1.（+）-和（-）-7- [3-（环戊氧基）-4-甲氧基苯基]六氢-3 H-吡咯烷-3-酮的不对称合成和立体化学分配

  摘要：

  葛兰素史克的高效磷酸二酯酶抑制剂1的不对称合成已通过9个步骤完成，总收率达16％。建议的原始策略包括作为关键步骤对映体纯的六元环状nitronates的甲硅烷基化4通过适当的硝基烯烃的高立体选择性[4 + 2] -环获得5至反式-1-苯基-2-（乙烯氧基）环己烷。所得5,6-二氢-4 H -1,2-恶嗪的官能化和随后中间体2中1,2-恶嗪环的立体选择性还原为吡咯烷酮框架提供了手性辅助醇的回收。

  DOI：

  10.1021/jo201331h

文献信息

• Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (−)-, and (±)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3<i>H</i>-pyrrolizin-3-one via Reductive Domino Transformations of 3-β-Carbomethoxyethyl-Substituted Six-Membered Cyclic Nitronates
  作者：Alexey Yu. Sukhorukov、Yaroslav D. Boyko、Yulia V. Nelyubina、Stephane Gerard、Sema L. Ioffe、Vladimir A. Tartakovsky

  DOI：10.1021/jo300955n

  日期：2012.6.15

  highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (−)-1 were performed

  开发了葛兰素史克的高效PDE IVb抑制剂1的简单三步不对称和外消旋合成方法。所建议的方法是基于3-β-羰基甲氧基乙基取代的六元环状硝酸盐的还原多米诺变换，可通过将适当的硝基烯烃立体选择性地[4 + 2]环加成成乙烯基醚来轻松实现。进行了对映体吡咯烷二酮（+）- 1和（-）- 1对PDE IVb抑制的体外研究。
• Synthesis of Substituted 5-(3-Hydroxypropyl)pyrrolidin-2-ones and Pyrrolizidinones from Nitroethane via C3 Functionalized 5,6-Dihydro-4H-1,2-oxazines: A Novel Approach to Some Analogues of the Antidepressant Rolipram
  作者：Sema Ioffe、Alexey Sukhorukov、Alexey Lesiv、Yulia Khomutova、Vladimir Tartakovsky

  DOI：10.1055/s-0029-1216806

  日期：2009.6

  groups and decarboxylation in the last stage. The efficiency of this strategy was demonstrated by the stereoselective synthesis of pyrrolizidinone rac-4, a highly efficient analogue of antidepressant Rolipram, from nitroethane. 5,6-dihydro-4H-1,2-oxazines - reduction - pyrrolidones - pyrrolizidinones - Rolipram

  容易获得[（5,6-二氢-4- ħ -1,2-恶嗪-3-基）甲基]丙二酸酯1转化成取代的5-（3-羟丙基）吡咯烷-2-酮2和pyrrolizidinones 3，这是用于有机和生物有机化学的多功能产品和中间体。所建议的合成序列包括对肟基片段的立体选择性两步还原，然后进行涉及CO 2 Me基团之一的分子内环化和最后阶段的脱羧。该策略的有效性通过吡咯嗪酮rac - 4（一种高效的抗抑郁药物来利普兰的类似物）从硝基乙烷的立体选择性合成得到证明。 5,6-二氢-4 H -1,2-恶嗪-还原-吡咯烷酮-吡咯烷酮-咯利普兰
• Design and Synthesis of Conformationally Constrained Analogs of 4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724) as Potent Inhibitors of cAMP-Specific Phosphodiesterase
  作者：Marcus F. Brackeen、Jeffrey A. Stafford、David J. Cowan、Peter J. Brown、Paul L. Domanico、Paul L. Feldman、Dudley Rose、Alan B. Strickland、James M. Veal、Margrith Verghese

  DOI：10.1021/jm00024a012

  日期：1995.11

  The synthesis and biological evaluation of cAMP-specific phosphodiesterase (PDE IV) inhibitors is described. The PDE TV inhibitor 4-(3-butoxy-4-methoxybenzyl)imidazolidin (Ro 20-1724, 2) was used as a template from which to design a set of rigid oxazolidinones, imidazolidinones, and pyrrolizidinones that mimic Ro 20-1724 but differ in the orientation of the carbonyl group. The endo isomer of each of these heterocycles was more potent than the exo isomer in an enzyme inhibition assay and a cellular assay, which measured TNF alpha secretion from activated human peripheral blood monocytes (HPBM). Imidazolidinone 4a inhibited human PDE I with a K-i of 27 nM and TNF alpha secretion from HPBM with an IC50 of 290 nM. By comparison, Ro 20-1724 is significantly less active in these assays with activities of 1930 and 1800 nM, respectively.
• Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3<i>H</i>-pyrrolizin-3-one
  作者：Alexey Yu. Sukhorukov、Yaroslav D. Boyko、Sema L. Ioffe、Yulia A. Khomutova、Yulia V. Nelyubina、Vladimir A. Tartakovsky

  DOI：10.1021/jo201331h

  日期：2011.10.7

  Asymmetric synthesis of GlaxoSmithKline’s highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization

  葛兰素史克的高效磷酸二酯酶抑制剂1的不对称合成已通过9个步骤完成，总收率达16％。建议的原始策略包括作为关键步骤对映体纯的六元环状nitronates的甲硅烷基化4通过适当的硝基烯烃的高立体选择性[4 + 2] -环获得5至反式-1-苯基-2-（乙烯氧基）环己烷。所得5,6-二氢-4 H -1,2-恶嗪的官能化和随后中间体2中1,2-恶嗪环的立体选择性还原为吡咯烷酮框架提供了手性辅助醇的回收。