(2R,3R,4R,5R)-N-butyloxycarbonyl-3,4-bis(benzyloxy)-5-<(benzyloxy)methyl>-2-(hydroxymethyl)pyrrolidine | 231618-88-5

• 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: (2R,3R,4R,5R)-N-butyloxycarbonyl-3,4-bis(benzyloxy)-5-<(benzyloxy)methyl>-2-(hydroxymethyl)pyrrolidine
• 英文别名: (2R,3R,4R,5R)-tert-butyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate；N-tert-butyloxycarbonyl-(2R,3R,4R,5R)-2-(hydroxy-methyl)-3,4-di-O-benzyl-5-(O-benzyl-methyl)-pyrrolidine；(2R,3R,4R,5R)-N-butyloxycarbonyl-(3,4-dibenzyloxy-5-benzyloxymethyl-2-hydroxymethyl)-pyrrolidine；tert-butyl (2R,3R,4R,5R)-2-(hydroxymethyl)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)pyrrolidine-1-carboxylate
• CAS: 231618-88-5
• 化学式: C₃₂H₃₉NO₆
• 分子量: 533.665
• InChiKey: SNEAODFDDGYHQI-SKKKGAJSSA-N

物化性质

• 沸点：
  634.7±55.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  39
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  77.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R,3R,4R,5R)-N-butyloxycarbonyl-3,4-bis(benzyloxy)-5-<(benzyloxy)methyl>-2-(hydroxymethyl)pyrrolidine 在 palladium on activated charcoal 盐酸 、 sodium azide 、 氢气 、 sodium cyanoborohydride 、 三乙胺 、 三氟乙酸 作用下， 以 吡啶 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.5h， 生成 OPT-66
  参考文献：
  名称：

  A Versatile Synthetic Strategy for the Preparation and Discovery of New Iminocyclitols as Inhibitors of Glycosidases

  摘要：

  A series of iminocyclitols was prepared using a versatile synthetic strategy, and their inhibition of glycosidases was evaluated using capillary electrophoresis. The study has demonstrated that remarkable specificities in enzyme inhibition can be achieved with small modifications on the aglycon side chain and the ring nitrogen. Among the compounds synthesized, (2R,3R,4R,5R)-N-methyl-2-(acetamidomethyl)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine was found to be very potent; against beta-N-acetylhexosaminidase P with the K-i value of 80 nM.

  DOI：

  10.1021/jo9902446
• 作为产物：
  描述：

  1-(tert-butyl-dimethyl-sylanyloxy)-2-deoxy-2-azido-3,4,6-tri-O-benzyl-5-oxo-D-mannitol 在 palladium on activated charcoal 四丁基氟化铵 、 氢气 、 sodium cyanoborohydride 、 对甲苯磺酸 、 三乙胺 作用下， 以 四氢呋喃 、 吡啶 、 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 8.0h， 生成 (2R,3R,4R,5R)-N-butyloxycarbonyl-3,4-bis(benzyloxy)-5-<(benzyloxy)methyl>-2-(hydroxymethyl)pyrrolidine
  参考文献：
  名称：

  Synthesis and High-Throughput Screening of N-Acetyl-β-hexosaminidase Inhibitor Libraries Targeting Osteoarthritis

  摘要：

  C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.

  DOI：

  10.1021/jo049355h

文献信息

• Iminocyclitol inhibitors of hexoaminidase and glycosidase
  申请人：The Scripps Research Institute

  公开号：US06774140B1

  公开（公告）日：2004-08-10

  Designed iminocylitols that have potent inhibition activity with respect to hexominidases and glycosides are disclosed.

  披露了设计的亚氨基糖醇，它们对己糖苷酶和苷具有强大的抑制活性。
• Rapid modifications of N-substitution in iminosugars: Development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease
  作者：Wei-Chieh Cheng、Chen-Yi Weng、Wen-Yi Yun、Shang-Yu Chang、Yu-Chun Lin、Fuu-Jen Tsai、Fu-Yung Huang、Yun-Ru Chen

  DOI：10.1016/j.bmc.2013.06.054

  日期：2013.9

  discovery of β-glucocerebrosidase (GCase) inhibitors and pharmacological chaperones for Gaucher disease is described. The N-aminobutyl DNJ-based iminosugar was synthesized and conjugating with a variety of carboxylic acids to generate a N-diversely substituted iminosugar-based library. Several members of this library were found to be nanomolar-range inhibitors of GCase; the inhibition constant Ki of

  描述了快速发现β-葡萄糖脑苷脂酶（GCase）抑制剂和戈谢病的药理伴侣蛋白。的Ñ -氨基丁基基于DNJ-亚氨基糖合成并与各种羧酸缀合，以产生Ñ -diversely取代的亚氨基糖的基于库。已发现该文库的几个成员是GCase的纳摩尔范围抑制剂。抑制常数K i发现最有效的为71 nM。尽管这些新分子在来自Gaucher患者来源的细胞系的N370S成纤维细胞中显示出合理的伴侣活性（1.5至1.9倍），但同时伴随着细胞α-葡萄糖苷酶活性的下降，这可能会限制其进一步的治疗潜力。接下来，将新开发的N-取代基与吡咯烷基支架组装在一起，以产生新的分子用于进一步评估。新的2,5-二脱氧-2,5-亚氨基d -mannitol（DMDP）基亚氨基糖22被发现显示出令人满意的活性的陪伴通过以增强的GCase活性的戈谢N370S细胞系2.2倍，而没有损害蜂窝α-葡萄糖苷酶活性。
• A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP
  作者：En-Lun Tsou、Yao-Ting Yeh、Pi-Hui Liang、Wei-Chieh Cheng

  DOI：10.1016/j.tet.2008.10.096

  日期：2009.1

  A practical method for the synthesis of five-membered iminocyclitols, pyrrolidine alkaloids bearing multiple hydroxyl substituents, has been developed. All of the eight key intermediates, enantiopure tri-O-benzyl cyclic nitrones, are prepared from four cheap, readily available D-aldopentoses. The nucleophilic addition of cyclic nitrones with vinyl magnesium chloride and TMSCN shows high 2,3-trans stereoselectivity. To construct the 2,3-cis configurations, inversion of the C-2 nitrile group is achieved via an elimination-reduction sequence. Using this approach, five isomers of DMDP and six isomers of ADMDP are prepared efficiently. In the biological evaluation, iminocyclitol 27 is a new and potent inhibitor against beta-hexosaminidase with an IC50 value of 0.2 mu M. (C) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and High-Throughput Screening of <i>N</i>-Acetyl-β-hexosaminidase Inhibitor Libraries Targeting Osteoarthritis
  作者：Junjie Liu、Mehdi M. D. Numa、Haitian Liu、Shi-Jung Huang、Pamela Sears、Alexander R. Shikhman、Chi-Huey Wong

  DOI：10.1021/jo049355h

  日期：2004.9.1

  C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.
• A Versatile Synthetic Strategy for the Preparation and Discovery of New Iminocyclitols as Inhibitors of Glycosidases
  作者：Maki Takebayashi、Sayoko Hiranuma、Yoshimi Kanie、Tetsuya Kajimoto、Osamu Kanie、Chi-Huey Wong

  DOI：10.1021/jo9902446

  日期：1999.7.1

  A series of iminocyclitols was prepared using a versatile synthetic strategy, and their inhibition of glycosidases was evaluated using capillary electrophoresis. The study has demonstrated that remarkable specificities in enzyme inhibition can be achieved with small modifications on the aglycon side chain and the ring nitrogen. Among the compounds synthesized, (2R,3R,4R,5R)-N-methyl-2-(acetamidomethyl)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine was found to be very potent; against beta-N-acetylhexosaminidase P with the K-i value of 80 nM.