dimethyl (4aS,9bS,10aR)-8-methoxy-5-(phenylsulfonyl)-3-oxo-4a,5,9b,10-tetrahydro-3H-oxazolo<3',4':1,5>pyrrolo<2,3-b>indole-10a-1H-carboxylate

• 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 (4aS,9bS,10aR)-8-methoxy-5-(phenylsulfonyl)-3-oxo-4a,5,9b,10-tetrahydro-3H-oxazolo<3',4':1,5>pyrrolo<2,3-b>indole-10a-1H-carboxylate
• 英文别名: methyl (1S,9R,14S)-8-(benzenesulfonyl)-4-methoxy-11-oxo-12-oxa-8,10-diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5-triene-14-carboxylate
• 化学式: C₂₁H₂₀N₂O₇S
• 分子量: 444.465
• InChiKey: KOQGHLSOPLAJQK-CDXJDZJCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  111
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  dimethyl (2R,3aS,8aR)-5-methoxy-8-(phenylsulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-1,2-dicarboxylate 在 三氟化硼乙醚 、 4,4'-二氨基二苯乙烯-2,2'-二磺酸 、 lithium diisopropyl amide 作用下， 以 二氯甲烷 为溶剂， 反应 9.0h， 生成 dimethyl (4aS,9bS,10aR)-8-methoxy-5-(phenylsulfonyl)-3-oxo-4a,5,9b,10-tetrahydro-3H-oxazolo<3',4':1,5>pyrrolo<2,3-b>indole-10a-1H-carboxylate
  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

文献信息

• Enantiospecific syntheses of .alpha.-(fluoromethyl)tryptophan analogs: interactions with tryptophan hydroxylase and aromatic L-amino acid decarboxylase
  作者：David E. Zembower、Judith A. Gilbert、Matthew M. Ames

  DOI：10.1021/jm00055a001

  日期：1993.2

  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.