S-(2-acetamidoethyl) (R)-3-(2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanamido)propanethioate | 1333123-44-6

• 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: S-(2-acetamidoethyl) (R)-3-(2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanamido)propanethioate
• CAS: 1333123-44-6
• 化学式: C₂₂H₃₂ClN₃O₆S
• 分子量: 502.032
• InChiKey: DTRSFQKHDMQWQB-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.69
• 重原子数：
  33.0
• 可旋转键数：
  11.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  122.83
• 氢给体数：
  3.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenylocta-2,7-dienoic acid 、 S-(2-acetamidoethyl) (R)-3-(2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanamido)propanethioate 在 三氟乙酸 、 4-二甲氨基吡啶 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 以12%的产率得到S-(2-acetamidoethyl) 3-((R)-3-(3-chloro-4-methoxyphenyl)-2-((2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenylocta-2,7-dienamido)propanamido)propanethioate
  参考文献：
  名称：

  Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module

  摘要：

  Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Cop analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues.

  DOI：

  10.1021/ja204716f
• 作为产物：
  描述：

  2-acetamidoethyl 3-(tert-butoxycarbonylamino)propanethioate 、 N-Boc-O-methyl-D-3-chlorotyrosine 在 三氟乙酸 、 4-二甲氨基吡啶 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 以63%的产率得到S-(2-acetamidoethyl) (R)-3-(2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanamido)propanethioate
  参考文献：
  名称：

  Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module

  摘要：

  Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Cop analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues.

  DOI：

  10.1021/ja204716f