3-<4-(1,3-dioxolan-2-yl)-1-oxo-3(S)-phenyl-2(S)-azidobutyl>-4(S)-(phenylmethyl)-2-oxazolidinone | 138662-92-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物
• 英文名称: 3-<4-(1,3-dioxolan-2-yl)-1-oxo-3(S)-phenyl-2(S)-azidobutyl>-4(S)-(phenylmethyl)-2-oxazolidinone
• 英文别名: (4S)-3-[(2S,3S)-2-azido-4-(1,3-dioxolan-2-yl)-3-phenylbutanoyl]-4-benzyl-1,3-oxazolidin-2-one
• CAS: 138662-92-7
• 化学式: C₂₃H₂₄N₄O₅
• 分子量: 436.467
• InChiKey: RRWPJMCEHXTGNK-ZJOUEHCJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32.0
• 可旋转键数：
  8.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  113.83
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  3-<4-(1,3-dioxolan-2-yl)-1-oxo-3(S)-phenyl-2(S)-azidobutyl>-4(S)-(phenylmethyl)-2-oxazolidinone 在 盐酸 、 3 A molecular sieve 、 sodium cyanoborohydride 、 溶剂黄146 、 乙酸乙酯 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 9.0h， 生成 (S)-2-((3S,4S)-3-Azido-2-oxo-4-phenyl-piperidin-1-yl)-hexanoic acid
  参考文献：
  名称：

  Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors

  摘要：

  The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleucinamide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)-[butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

  DOI：

  10.1021/jm00083a006
• 作为产物：
  描述：

  benzyl 4-(1,3-dioxolan-2-yl)-3-phenylbutanoate 在 sodium hydroxide 、 2,4,6-三异丙基苯磺酰叠氮化物 、 三甲基乙酰氯 、 双(三甲基硅烷基)氨基钾 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 11.67h， 生成 3-<4-(1,3-dioxolan-2-yl)-1-oxo-3(S)-phenyl-2(S)-azidobutyl>-4(S)-(phenylmethyl)-2-oxazolidinone
  参考文献：
  名称：

  Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors

  摘要：

  The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleucinamide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)-[butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

  DOI：

  10.1021/jm00083a006