methyl N-(benzyloxycarbonyl)-3-amino-2-oxo-4-melylpentanoate | 157683-58-4

• 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: methyl N-(benzyloxycarbonyl)-3-amino-2-oxo-4-melylpentanoate
• 英文别名: methyl (3S)-4-methyl-2-oxo-3-(phenylmethoxycarbonylamino)pentanoate
• CAS: 157683-58-4
• 化学式: C₁₅H₁₉NO₅
• 分子量: 293.32
• InChiKey: UDDFFEJHXMBHAS-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl N-(benzyloxycarbonyl)-3-amino-2-oxo-4-melylpentanoate 在 三氯化硼 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 benzyl N-[(2S)-1-[[(3S)-1-(benzylamino)-4-methyl-1,2-dioxopentan-3-yl]amino]-1-oxopentan-2-yl]carbamate
  参考文献：
  名称：

  Development of α-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease

  摘要：

  Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1 ' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3 angstrom crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.12.053
• 作为产物：
  描述：

  在 二甲基二环氧乙烷 作用下， 以 丙酮 为溶剂， 生成 methyl N-(benzyloxycarbonyl)-3-amino-2-oxo-4-melylpentanoate
  参考文献：
  名称：

  First synthesis of enantiomerically pure N-protected β-amino-α-keto esters from α-amino acids and dipeptides

  摘要：

  A racemization-free route from N-protected alpha-amino acids and dipeptides to N-protected beta-amino-alpha-keto esters is described, involving the sequence: diazoketone formation. Wolff rearrangement in methanol, diazo transfer, and oxidation with dimethyldioxirane.

  DOI：

  10.1016/s0957-4166(00)86171-6

文献信息

• Chemoselective Conversion from α-Hydroxy Acids to α-Keto Acids Enabled by Nitroxyl-Radical-Catalyzed Aerobic Oxidation
  作者：Keisuke Furukawa、Haruki Inada、Masatoshi Shibuya、Yoshihiko Yamamoto

  DOI：10.1021/acs.orglett.6b01964

  日期：2016.9.2

  The chemoselective oxidation of α-hydroxy acids to α-keto acids catalyzed by 2-azaadamantane N-oxyl (AZADO), a nitroxyl radical catalyst, is described. Although α-keto acids are labile and can easily release CO2 under oxidation conditions, the use of molecular oxygen as a cooxidant enables the desired chemoselective oxidation.

  描述了由2-氮杂金刚烷N-氧基（AZADO）（一种硝基氧基自由基催化剂）催化的α-羟基酸到α-酮酸的化学选择性氧化。尽管α-酮酸不稳定并且可以在氧化条件下轻易释放CO 2，但是使用分子氧作为助氧化剂可以实现所需的化学选择性氧化。
• Synthesis of cyanoketophosphoranes, precursors of β-amino-α-keto-esters from UNCAs
  作者：Marielle Paris、Catherine Pothion、Christine Michalak、Jean Martinez、Jean-Alain Fehrentz

  DOI：10.1016/s0040-4039(98)01504-4

  日期：1998.9

  Cyanomethylene triphenylphosphoranes of N-protected amino acids were synthesized from the corresponding N-urethane protected α-amino acid N-carboxyanhydrides (UNCAs) by reaction with cyanomethyltriphenylphosphonium chloride in good yields. These compounds are precursors of α-keto esters which are candidates for mimicking the tetrahedric transition state in enzyme inhibitors.

  由N-氨基甲酸酯保护的α-氨基酸N-羧基酸酐（UNCA）通过与氰基甲基三苯基chloride氯化物反应，以高收率合成了N-保护氨基酸的氰基亚甲基三苯基膦。这些化合物是α-酮酯的前体，它们是模拟酶抑制剂中四面体过渡态的候选物。
• Development of α-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease
  作者：Youngchool Choe、Linda S. Brinen、Mark S. Price、Juan C. Engel、Meinolf Lange、Corinna Grisostomi、Scott G. Weston、Peter V. Pallai、Hong Cheng、Larry W. Hardy、David S. Hartsough、Marsha McMakin、Robert F. Tilton、Carmen M. Baldino、Charles S. Craik

  DOI：10.1016/j.bmc.2004.12.053

  日期：2005.3

  Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1 ' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3 angstrom crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization. (c) 2005 Elsevier Ltd. All rights reserved.
• First synthesis of enantiomerically pure N-protected β-amino-α-keto esters from α-amino acids and dipeptides
  作者：Paul Darkins、Noreen McCarthy、M. Anthony、McKervey、Kevin O'Donnell、Tao Ye、Brian Walker

  DOI：10.1016/s0957-4166(00)86171-6

  日期：1994.1

  A racemization-free route from N-protected alpha-amino acids and dipeptides to N-protected beta-amino-alpha-keto esters is described, involving the sequence: diazoketone formation. Wolff rearrangement in methanol, diazo transfer, and oxidation with dimethyldioxirane.