tert-butyl (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-5H-[1,3]dioxino[5,4-b]pyridine-5-carboxylate | 505085-63-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-5H-[1,3]dioxino[5,4-b]pyridine-5-carboxylate
• 英文别名: tert-butyl (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-[1,3]dioxino[5,4-b]pyridine-5-carboxylate
• CAS: 505085-63-2
• 化学式: C₁₄H₂₃NO₄
• 分子量: 269.341
• InChiKey: QWHMDBPGFPEMDB-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-5H-[1,3]dioxino[5,4-b]pyridine-5-carboxylate 在 吡啶 、 potassium osmate(VI) 、 N-甲基吲哚酮 、 对甲苯磺酸 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 4.0h， 生成 tert-butyl (2S,3S,4S,5S)-3,4,5-triacetyloxy-2-(acetyloxymethyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Biological Properties of d- and l-1-Deoxyazasugars

  摘要：

  L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyldonojirimycin (ido-DNJ) were prepared according to prior methods for the D-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although D-DNJ and D-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the nM range, L-DNJ and L-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the PM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. D-manno-DNJ is known as a much better inhibitor of alpha-L-fucosidase than a-mannosidase, while L-allo-DNJ was a better inhibitor than D-manno-DNJ of alpha-mannosidase. L-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-L-fucosidase with a K-i value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-L-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. D-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC50 = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while D-DNJ inhibiting alpha-glucosidase (IC50 = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although L-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC50 = 64 mu M), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.

  DOI：

  10.1021/jm0495881
• 作为产物：
  描述：

  (4aS,7S,8aR)-2,2-Dimethyl-7-((R)-toluene-4-sulfinyl)-hexahydro-[1,3]dioxino[5,4-b]pyridine-5-carboxylic acid tert-butyl ester 在 三乙烯二胺 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以45%的产率得到tert-butyl (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-5H-[1,3]dioxino[5,4-b]pyridine-5-carboxylate
  参考文献：
  名称：

  Diastereoselective Route to Piperidine and Indolizidine Scaffolds From Enantiopure Vinylsulfinyl-Containing Amino Alcohols

  摘要：

  A new route to functionalized piperidine and indolizidine scaffolds, based on the diastereoselective intramolecular Michael cyclization of vinyl-sulfinyl-containing amino alcohols 1-3, has been developed. Pyrolytic elimination of the resulting cycloadducts resulted in the regioselective formation of the corresponding tetrahydropyridines and indolizidines. The observed regiochemical course of this process can be explained mainly in terms of the steric bias imposed by the disposition of the arylsulfinyl group and the concerted syn mechanism accepted for this kind of elimination.

  DOI：

  10.1002/1099-0690(200301)2003:1<217::aid-ejoc217>3.0.co;2-w

文献信息

• Chiral disubstituted piperidinyl ureas: a class of dual diacylglycerol lipase-α and ABHD6 inhibitors
  作者：Hui Deng、Tom van der Wel、Richard J. B. H. N. van den Berg、Adrianus M. C. H. van den Nieuwendijk、Freek J. Janssen、Marc P. Baggelaar、Hermen S. Overkleeft、Mario van der Stelt

  DOI：10.1039/c7md00029d

  日期：——

  Inhibitors of diacylglycerol lipases and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality

  二酰基甘油脂肪酶和含有α，β-水解酶结构域的蛋白质6（ABHD6）的抑制剂是开发用于代谢和神经退行性疾病的治疗剂的潜在先导。在这里，我们报告的手性，羟基化的2-苄基哌啶作为DAGLα和ABHD6的双重抑制剂的三唑脲的对映选择性合成与结构活性关系。如使用生化分析和竞争活性所确定的那样，带有C2取代基的碳的手性以及羟基的位置（在C5处耐受，但在C3处不耐受）对DAGLα和ABHD6的抑制活性都有深远影响-基于小鼠脑提取物的蛋白质谱分析。
• Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors
  作者：Richard J. B. H. N. van den Berg、Tom Wennekes、Amar Ghisaidoobe、Wilma E. Donker-Koopman、Anneke Strijland、Rolf G. Boot、Gijsbert A. van der Marel、Johannes M. F. G. Aerts、Herman S. Overkleeft

  DOI：10.1021/ml200050s

  日期：2011.7.14

  N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with

  葡萄糖神经酰胺合酶 (GCS) 是一种已获批准的治疗戈谢病的药物靶点，被认为是对抗其他人类疾病（包括 2 型糖尿病）的有效靶点。临床药物N-丁基脱氧野尻霉素 (Zavesca) 被认为通过模拟其底物神经酰胺来抑制。在这项工作中，我们证明，与该模型中提出的相反，脱氧野尻霉素核心的 C2-羟基对于 GCS 抑制很重要。在这里，我们表明 C6-OH 似乎不那么重要，这可能为开发对其他糖加工酶（特别是作用于葡萄糖神经酰胺的水解酶）具有较低亲和力（与 Zavesca 相比）的 GCS 抑制剂制定指导方针。
• Diastereoselective Route to Piperidine and Indolizidine Scaffolds From Enantiopure Vinylsulfinyl-Containing Amino Alcohols
  作者：Raúl Montoro、Francesc Márquez、Amadeu Llebaria、Antonio Delgado

  DOI：10.1002/1099-0690(200301)2003:1<217::aid-ejoc217>3.0.co;2-w

  日期：2003.1

  A new route to functionalized piperidine and indolizidine scaffolds, based on the diastereoselective intramolecular Michael cyclization of vinyl-sulfinyl-containing amino alcohols 1-3, has been developed. Pyrolytic elimination of the resulting cycloadducts resulted in the regioselective formation of the corresponding tetrahydropyridines and indolizidines. The observed regiochemical course of this process can be explained mainly in terms of the steric bias imposed by the disposition of the arylsulfinyl group and the concerted syn mechanism accepted for this kind of elimination.
• Biological Properties of <scp>d</scp>- and <scp>l</scp>-1-Deoxyazasugars
  作者：Atsushi Kato、Noriko Kato、Erika Kano、Isao Adachi、Kyoko Ikeda、Liang Yu、Tadashi Okamoto、Yasunori Banba、Hidekazu Ouchi、Hiroki Takahata、Naoki Asano

  DOI：10.1021/jm0495881

  日期：2005.3.1

  L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyldonojirimycin (ido-DNJ) were prepared according to prior methods for the D-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although D-DNJ and D-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the nM range, L-DNJ and L-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the PM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. D-manno-DNJ is known as a much better inhibitor of alpha-L-fucosidase than a-mannosidase, while L-allo-DNJ was a better inhibitor than D-manno-DNJ of alpha-mannosidase. L-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-L-fucosidase with a K-i value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-L-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. D-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC50 = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while D-DNJ inhibiting alpha-glucosidase (IC50 = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although L-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC50 = 64 mu M), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.