tert-butyl (4S,5S)-5-[(2S)-2-amino-2-benzyl-3-methoxy-3-oxopropyl]-4-benzyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | 173240-65-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl (4S,5S)-5-[(2S)-2-amino-2-benzyl-3-methoxy-3-oxopropyl]-4-benzyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 173240-65-8
• 化学式: C₂₈H₃₈N₂O₅
• 分子量: 482.62
• InChiKey: MSJOEVIYTLKXMN-LXWOLXCRSA-N

物化性质

• 沸点：
  573.4±50.0 °C(Predicted)
• 密度：
  1.123±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  91.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl (4S,5S)-5-[(2S)-2-amino-2-benzyl-3-methoxy-3-oxopropyl]-4-benzyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 在 盐酸 、 四(三苯基膦)钯 、 jones reagent 、 氨 、 双(三甲基硅烷基)氨基钾 、 5,5-二甲基-1,3-环己二酮 、 三乙胺 作用下， 以 四氢呋喃 、 氯仿 、 甲苯 、 乙腈 为溶剂， 反应 51.17h， 生成 methyl (2R)-2-[(5S)-5-[(5S)-5-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-benzyl-4-oxo-1H-pyrrol-3-yl]-5-(2-methylpropyl)-4-oxo-1H-pyrrol-3-yl]-3-phenylpropanoate
  参考文献：
  名称：

  Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activity: Evidence for Improved Transport

  摘要：

  Pyrrolinone-based peptidomimetics, the first mimics of beta-strands, are potent inhibitors of HIV-1 protease. Importantly, the bis(pyrrolinones) described herein proved to be more active in cellular antiviral assays compared with an analogous peptide-derived inhibitor even though they are less effective in inhibiting the isolated protease. These results suggest that pyrrolinone inhibitors offer better transport properties than the corresponding peptide-based peptidomimetics; we attribute this effect to decreased solvation of the mimetics. Structure-activity relationships for the pyrrolinones correlate well with those reported for related peptides, consistent with similar modes of binding.

  DOI：

  10.1021/ja00150a011
• 作为产物：
  描述：

  prop-2-enyl (2R,4S)-4-benzyl-2-tert-butyl-4-[(2S,3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutyl]-5-oxo-1,3-oxazolidine-3-carboxylate 在 sodium hydroxide 、 四(三苯基膦)钯 、 potassium carbonate 、 5,5-二甲基-1,3-环己二酮 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 72.0h， 生成 tert-butyl (4S,5S)-5-[(2S)-2-amino-2-benzyl-3-methoxy-3-oxopropyl]-4-benzyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
  参考文献：
  名称：

  恶唑烷酮烯醇铝与环氧化物的对映体烷基化：未编码的高丝氨酸类似物的制备

  摘要：

  Karady / Seebach恶唑烷酮烯醇烯酸酯与环氧化物的烷基化，由2.1当量的二乙基氯化铝促进，以中等至良好的收率和高非对映选择性提供开环加合物。该方法为未编码的高丝氨酸类似物提供了有效的方法，并扩大了不对称合成中容易获得的恶唑烷酮的实用性。

  DOI：

  10.1016/0040-4039(94)88404-8

文献信息

• Design, Synthesis, and Biological Evaluation of Monopyrrolinone-Based HIV-1 Protease Inhibitors
  作者：Amos B. Smith、Louis-David Cantin、Alexander Pasternak、Lisa Guise-Zawacki、Wenquin Yao、Adam K. Charnley、Joseph Barbosa、Paul A. Sprengeler、Ralph Hirschmann、Sanjeev Munshi、David B. Olsen、William A. Schleif、Lawrence C. Kuo

  DOI：10.1021/jm0204587

  日期：2003.5.1

  The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold is described. Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts. The most potent

  基于3,5,5的一系列HIV-1蛋白酶抑制剂[（-）-6，（-）-7，（-）-23，（+）-24]的设计，合成和生物学评估描述了-三取代的吡咯啉-4-酮支架。相对于较早的基于双吡咯啉酮及其肽对应物的抑制剂，单吡咯啉酮支架的使用导致抑制剂具有改善的细胞运输特性。最有效的抑制剂（-）-7在犬中显示13％的口服生物利用度。与野生型HIV-1蛋白酶共结晶的单吡咯啉酮化合物的X射线结构分析提供了有关抑制剂与HIV-1酶之间相互作用的有价值的信息。在每种情况下，抑制剂都假定P2'-P1取代基具有相似的取向，以及吡咯烷酮NH与Asp225的意外氢键。与S2口袋的互动，然而，并不是最佳的，正如在三种抑制剂-酶复合物中的两种中包含水分子所说明的那样。通过用第二代和第三代抑制剂置换水分子来增加亲和力的努力并未证明是成功的。该项目的成功缺乏证明了难以准确预测影响和建立结合亲和力的许多变量的困难。将三种复合物中抑
• Enantioretentive alkylation of oxazolidinone aluminum enolates with epoxides: Preparation of uncoded homoserine analogs
  作者：Amos B. Smith、Alexander Pasternak、Akihisa Yokoyama、Ralph Hirschmann

  DOI：10.1016/0040-4039(94)88404-8

  日期：1994.11

  The alkylation of Karady/Seebach oxazolidinone enolates with epoxides, promoted by 2.1 equivalents of diethylaluminum chloride, furnishes ring-opened adducts in moderate-to-good yields with high diastereoselectivity. The method provides an effective approach to uncoded homoserine analogs and expands the utility of readily available oxazolidinones in asymmetric synthesis.

  Karady / Seebach恶唑烷酮烯醇烯酸酯与环氧化物的烷基化，由2.1当量的二乙基氯化铝促进，以中等至良好的收率和高非对映选择性提供开环加合物。该方法为未编码的高丝氨酸类似物提供了有效的方法，并扩大了不对称合成中容易获得的恶唑烷酮的实用性。
• Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2′ side chains
  作者：Amos B. Smith、Adam K. Charnley、Hironori Harada、Jason J. Beiger、Louis-David Cantin、Craig S. Kenesky、Ralph Hirschmann、Sanjeev Munshi、David B. Olsen、Mark W. Stahlhut、William A. Schleif、Lawrence C. Kuo

  DOI：10.1016/j.bmcl.2005.11.011

  日期：2006.2

  A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2' side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.
• An Orally Bioavailable Pyrrolinone Inhibitor of HIV-1 Protease:  Computational Analysis and X-ray Crystal Structure of the Enzyme Complex
  作者：Amos B. Smith、Ralph Hirschmann、Alexander Pasternak、Wenquing Yao、Paul A. Sprengeler、M. Katharine Holloway、Lawrence C. Kuo、Zhongguo Chen、Paul L. Darke、William A. Schleif

  DOI：10.1021/jm970195u

  日期：1997.8.1
• Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activity: Evidence for Improved Transport
  作者：Amos B Smith、Ralph Hirschmann、Alexander Pasternak、Mark C. Guzman、Akihisa Yokoyama、Paul A. Sprengeler、Paul L. Darke、Emilio A. Emini、William A. Schleif

  DOI：10.1021/ja00150a011

  日期：1995.11

  Pyrrolinone-based peptidomimetics, the first mimics of beta-strands, are potent inhibitors of HIV-1 protease. Importantly, the bis(pyrrolinones) described herein proved to be more active in cellular antiviral assays compared with an analogous peptide-derived inhibitor even though they are less effective in inhibiting the isolated protease. These results suggest that pyrrolinone inhibitors offer better transport properties than the corresponding peptide-based peptidomimetics; we attribute this effect to decreased solvation of the mimetics. Structure-activity relationships for the pyrrolinones correlate well with those reported for related peptides, consistent with similar modes of binding.