dimethyl (2S,3aS,8aR)-2-(hydroxymethyl)-8-(phenylsulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate | 145919-18-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: dimethyl (2S,3aS,8aR)-2-(hydroxymethyl)-8-(phenylsulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate
• 英文别名: dimethyl (2S,3aR,8bS)-4-(benzenesulfonyl)-2-(hydroxymethyl)-3a,8b-dihydro-1H-pyrrolo[2,3-b]indole-2,3-dicarboxylate
• CAS: 145919-18-2
• 化学式: C₂₁H₂₂N₂O₇S
• 分子量: 446.481
• InChiKey: JXTRNWXOILNOOV-CDXJDZJCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  122
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  dimethyl (2S,3aS,8aR)-2-(hydroxymethyl)-8-(phenylsulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate 在 4,4'-二氨基二苯乙烯-2,2'-二磺酸 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 α(R)-(fluoromethyl)-N_b-(methoxycarbonyl)-N_a-(phenylsulfonyl)tryptophan methyl ester
  参考文献：
  名称：

  Enantiospecific syntheses of .alpha.-(fluoromethyl)tryptophan analogs: interactions with tryptophan hydroxylase and aromatic L-amino acid decarboxylase

  摘要：

  Alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Our goal is to utilize antagonists of the serotonin-producing enzymes (tryptophan hydroxylase and AADC) as the basis for a chemotherapeutic approach to the treatment of carcinoid tumors, a rare tumor type characterized by the overproduction of serotonin. We report here an enantiospecific synthesis of alpha(S)-(fluoromethyl)tryptophan [(S)-11a] and alpha(S)-(fluoromethyl)-5-hydroxytryptophan [(S)-11b], as well as the (R)-enantiomers, based upon recent methodology involving the face-selective alkylation of cyclic tryptophan tautomers. Our synthetic route provided both enantiomers of 11a and 11b with greater than 97% enantiomeric purity based upon evaluation of the NMR spectra of their Mosher's acid derivatives. (S)-11a was evaluated as a substrate for P815 tryptophan hydroxylase and determined to have an apparent K(m) of 4.31 +/- 1.07 mM, essentially half the value previously reported for the racemic mixture of 11a with rat brain stem tryptophan hydroxylase. (R)-11a was not a substrate for P815 tryptophan hydroxylase. (S)-11b was evaluated as an enzyme-activated irreversible inhibitor of murine liver AADC and determined to have a K(I) of 24.3 +/- 3.01 muM and a k2 of 2.26 +/- 0.44 min-1. (R)-11b was not an inhibitor of murine liver AADC.

  DOI：

  10.1021/jm00055a001
• 作为产物：
  描述：

  dimethyl (2S,3aS,8aR)-8-(phenylsulfonyl)-2-<<2-(trimethylsilyl)ethoxy>methyl>-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate 在 三氟化硼乙醚 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以56%的产率得到dimethyl (2S,3aS,8aR)-2-(hydroxymethyl)-8-(phenylsulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate
  参考文献：
  名称：

  Enantiospecific syntheses of .alpha.-(fluoromethyl)tryptophan analogs: interactions with tryptophan hydroxylase and aromatic L-amino acid decarboxylase

  摘要：

  Alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Our goal is to utilize antagonists of the serotonin-producing enzymes (tryptophan hydroxylase and AADC) as the basis for a chemotherapeutic approach to the treatment of carcinoid tumors, a rare tumor type characterized by the overproduction of serotonin. We report here an enantiospecific synthesis of alpha(S)-(fluoromethyl)tryptophan [(S)-11a] and alpha(S)-(fluoromethyl)-5-hydroxytryptophan [(S)-11b], as well as the (R)-enantiomers, based upon recent methodology involving the face-selective alkylation of cyclic tryptophan tautomers. Our synthetic route provided both enantiomers of 11a and 11b with greater than 97% enantiomeric purity based upon evaluation of the NMR spectra of their Mosher's acid derivatives. (S)-11a was evaluated as a substrate for P815 tryptophan hydroxylase and determined to have an apparent K(m) of 4.31 +/- 1.07 mM, essentially half the value previously reported for the racemic mixture of 11a with rat brain stem tryptophan hydroxylase. (R)-11a was not a substrate for P815 tryptophan hydroxylase. (S)-11b was evaluated as an enzyme-activated irreversible inhibitor of murine liver AADC and determined to have a K(I) of 24.3 +/- 3.01 muM and a k2 of 2.26 +/- 0.44 min-1. (R)-11b was not an inhibitor of murine liver AADC.

  DOI：

  10.1021/jm00055a001