trans-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester | 279218-33-6

• 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: trans-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester
• 英文别名: 1-O-benzyl 4-O-tert-butyl (3aS,6aR)-5-oxo-3,3a,6,6a-tetrahydro-2H-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylate
• CAS: 279218-33-6
• 化学式: C₁₉H₂₄N₂O₅
• 分子量: 360.41
• InChiKey: MQQNOQICFOIXHH-LSDHHAIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  trans-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester 在 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 1.59h， 生成 rel-(3aS,6S,6aR)-6-methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxohexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality

  摘要：

  The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.

  DOI：

  10.1021/jm0102203
• 作为产物：
  描述：

  H-A2bu(Z)-OH 在 N-甲基吗啉 、 sodium hydroxide 、 sodium tetrahydroborate 、 草酰氯 、 四甲基乙二胺 、 叔丁基氯化镁 、 二甲基亚砜 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 46.21h， 生成 trans-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 1. The α-Methyl-trans-lactam Template

  摘要：

  Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta -methyl-, desmethyl-, and alpha -methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown that these inhibitors can bind covalently and reversibly to the viral enzyme in a time-dependent manner by a mechanism which is consistent; with acylation of HCMV delta Ala protease at the active site nucleophile Ser 132. SAR in this series of pyrrolidine-5,5-trans-lactams has defined the relative stereochemisty of the methyl substituent adjacent to the lactam carbonyl, the functionality on the lactam nitrogen, and the mechanism of action of this novel series of serine protease inhibitors against the HCMV dAla protease. Activity decreases on moving from the alpha -methyl to the desmethyl to the beta -methyl series. This selectivity is the opposite of that observed for these templates against the elastase and thrombin enzymes. The activity against HCMV delta Ala protease is the greatest with inhibitors based on the Cbz-protected alpha -methyl-5,5-trans-lactam template which have low micromolar activity against the viral enzyme.

  DOI：

  10.1021/jm000078q

文献信息

• Pyrrolidine-5,5-<i>trans</i>-lactams 3. Alternative RegiochemicalOutcome of the Acyl-Iminium Coupling Reaction.
  作者：David Andrews、Alan Borthwick、Helene Chaignot、Paul Jones、J. Robinson、Pritom Shah、Martin Slater、Richard Upton

  DOI：10.1055/s-2003-40879

  日期：2003.8

  Enantio- and regioselective syntheses of the pyrrolidine 5,5-trans-lactams benzyl (3aS,6aR)-6,6-dimethyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate and benzyl (3aS,6aR)-6S-ethyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate from a common intermediate 2-ethoxy-3S-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-carboxylic acid benzyl ester are reported. The key step in both syntheses is the acyl iminium ion mediated condensation of the pyrrolidine with a ketene acetal.

  报道了从共同中间体2-乙氧基-3S-(2,2,2-三氟乙酰氨基)-哌啶-1-羧酸苄酯合成的对映体选择性和区域选择性合成吡咯烷5,5-trans-内酯，分别是苄基(3aS,6aR)-6,6-二甲基-5-氧基六氢吡咯[3,2-b]吡咯-1(2H)-羧酸酯和苄基(3aS,6aR)-6S-乙基-5-氧基六氢吡咯[3,2-b]吡咯-1(2H)-羧酸酯。这两种合成的关键步骤是哌啶与酮烯醇缩合的酰基亚氨离子介导的反应。
• Stereoselective synthesis of gem-dimethyl-5,5-pyrrolidine-trans-lactam (5-oxo-hexahydropyrrolo[3,2-b]pyrrole)
  作者：Alan D Borthwick、David E Davies、Anne M Exall、Andrew M.K Pennell、Jemima J Richards

  DOI：10.1016/s0040-4039(01)01410-1

  日期：2001.9

  The gem-dimethyl-trans-lactam 6 could be prepared by alkylation of the beta -methyl isomer 7 but not by alkylation of the alpha -isomer 5. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Borthwick, Alan D.; Crame, Andrew J.; Davies, David E., Synlett, 2000, # 4, p. 504 - 508
  作者：Borthwick, Alan D.、Crame, Andrew J.、Davies, David E.、Exall, Anne M.、Jackson, Deborah L.、Mason, Andrew M.、Pennell, Andrew M. K.、Weingarten, Gordon G.

  DOI：——

  日期：——
• Syntheses of templates derived from pyrrolidine trans -lactams as potential serine protease inhibitors
  作者：Simon J.F. Macdonald、Graham G.A. Inglis、Deborah Bentley、Michael D. Dowle

  DOI：10.1016/s0040-4039(02)01002-x

  日期：2002.7

  The synthesis of templates derived from pyrrolidine traps-lactams as potential serine protease inhibitors is described. (C) 2002 Elsevier Science Ltd. All rights reserved.
• METHOD OF INHIBITING SERINE PROTEASE ENZYMES
  申请人：GLAXO GROUP LIMITED

  公开号：EP1015454A1

  公开（公告）日：2000-07-05