methyl (1R,9R,10R,12R,20R)-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.7.1.01,9.02,7.016,20]icosa-2(7),3,5,13-tetraene-10-carboxylate | 1417782-81-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 鸡蛋花型生物碱
• 英文名称: methyl (1R,9R,10R,12R,20R)-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.7.1.01,9.02,7.016,20]icosa-2(7),3,5,13-tetraene-10-carboxylate
• CAS: 1417782-81-0
• 化学式: C₂₄H₃₂N₂O₄
• 分子量: 412.529
• InChiKey: YYUPQAZRUQDXQF-FCWDYNECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  62.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  catharanthine sulfate 、 methyl (1R,9R,10R,12R,20R)-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.7.1.01,9.02,7.016,20]icosa-2(7),3,5,13-tetraene-10-carboxylate 在 盐酸 、 iron(III) chloride hexahydrate 、 sodium tetrahydroborate 、 ferric(III)oxalate hexahydrate 、 氧气 作用下， 以 2,2,2-三氟乙醇 、 水 为溶剂， 反应 2.5h， 以20%的产率得到methyl (1R,9R,10R,12R,20R)-12-ethyl-4-[(13S,15R,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.7.1.01,9.02,7.016,20]icosa-2,4,6,13-tetraene-10-carboxylate
  参考文献：
  名称：

  Total Synthesis and Evaluation of Vinblastine Analogues Containing Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign

  摘要：

  The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.

  DOI：

  10.1021/jm3014376
• 作为产物：
  描述：

  6-甲氧基-1-甲基-1H-吲哚-3-甲醛 在 劳森试剂 、 4-二甲氨基吡啶 、 ammonium hydroxide 、 sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 氢气 、 双氧水 、 trimethoxonium tetrafluoroborate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 156.58h， 生成 methyl (1R,9R,10R,12R,20R)-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.7.1.01,9.02,7.016,20]icosa-2(7),3,5,13-tetraene-10-carboxylate
  参考文献：
  名称：

  Total Synthesis and Evaluation of Vinblastine Analogues Containing Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign

  摘要：

  The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.

  DOI：

  10.1021/jm3014376