(-)-(1S)-5-benzyloxy-3-tert-butoxycarbonyl-1-chloromethyl-8-cyano-1,2-dihydro-3H-benz[e]indole | 178877-27-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (-)-(1S)-5-benzyloxy-3-tert-butoxycarbonyl-1-chloromethyl-8-cyano-1,2-dihydro-3H-benz[e]indole
• 英文别名: Lmtxzxiawfmhtg-ljqanchmsa-；tert-butyl (1S)-1-(chloromethyl)-8-cyano-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-3-carboxylate
• CAS: 178877-27-5
• 化学式: C₂₆H₂₅ClN₂O₃
• 分子量: 448.949
• InChiKey: LMTXZXIAWFMHTG-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  62.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (-)-(1S)-5-benzyloxy-3-tert-butoxycarbonyl-1-chloromethyl-8-cyano-1,2-dihydro-3H-benz[e]indole 在 palladium on activated charcoal 氢气 、 碳酸氢钠 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 为溶剂， 反应 11.5h， 生成 tert-butyl (1R,13S)-4-cyano-8-oxo-11-azatetracyclo[8.4.0.01,13.02,7]tetradeca-2(7),3,5,9-tetraene-11-carboxylate
  参考文献：
  名称：

  Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one Alkylation Subunit:  Hammett Quantitation of the Magnitude of Electronic Effects on Functional Reactivity

  摘要：

  The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in efforts that establish the magnitude of potential electronic effects on the functional reactivity of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors followed by 5-exo-trig aryl radical-alkene cyclization for synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation for introduction of the activated cyclopropane. The most concise approach provided the CCBI subunit and its immediate precursor in 14-15 steps in superb overall conversions (15-20%). Resolution of an immediate CCBI precursor and its incorporation into both enantiomers of 34-39, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-CCBI (25) revealed that introduction of the C7 nitrile slowed the rate of solvolysis but only to a surprisingly small extent. Classical Hammett quantitation of the effect provided a remarkably small rho (-0.3), indicating an exceptionally small C7 substituent electronic effect on functional reactivity. Additional kinetic studies of acid-catalyzed nucleophilic addition proved inconsistent with C4 carbonyl protonation as the slow and rate-determining step but consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction, This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. Consistent with past studies, a direct relationship between solvolysis stability and cytotoxic potency was observed with the CCBI-derived agents providing the most potent analogs in the CBI series, and these observations were related to the predictable Hammett substituent effects. For the natural enantiomers, this unusually small electronic effect on functional reactivity had no perceptible effect on their DNA alkylation selectivity. Similar effects of the C7 cyano substituent on the unnatural enantiomers were observed, and they proved to be 4-10x more effective than the corresponding CBI-based unnatural enantiomers and 4-70x less potent than the CCBI natural enantiomers.

  DOI：

  10.1021/jo9605298
• 作为产物：
  描述：

  7-氰基-4-(苯基甲氧基)-2-萘羧酸乙酯 在 四氯化碳 、 lithium hydroxide 、 N-碘代丁二酰亚胺 、 叠氮磷酸二苯酯 、 三正丁基氢锡 、 sodium hydride 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 三苯基膦 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 苯 为溶剂， 反应 53.92h， 生成 (-)-(1S)-5-benzyloxy-3-tert-butoxycarbonyl-1-chloromethyl-8-cyano-1,2-dihydro-3H-benz[e]indole
  参考文献：
  名称：

  Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one Alkylation Subunit:  Hammett Quantitation of the Magnitude of Electronic Effects on Functional Reactivity

  摘要：

  The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in efforts that establish the magnitude of potential electronic effects on the functional reactivity of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors followed by 5-exo-trig aryl radical-alkene cyclization for synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation for introduction of the activated cyclopropane. The most concise approach provided the CCBI subunit and its immediate precursor in 14-15 steps in superb overall conversions (15-20%). Resolution of an immediate CCBI precursor and its incorporation into both enantiomers of 34-39, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-CCBI (25) revealed that introduction of the C7 nitrile slowed the rate of solvolysis but only to a surprisingly small extent. Classical Hammett quantitation of the effect provided a remarkably small rho (-0.3), indicating an exceptionally small C7 substituent electronic effect on functional reactivity. Additional kinetic studies of acid-catalyzed nucleophilic addition proved inconsistent with C4 carbonyl protonation as the slow and rate-determining step but consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction, This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. Consistent with past studies, a direct relationship between solvolysis stability and cytotoxic potency was observed with the CCBI-derived agents providing the most potent analogs in the CBI series, and these observations were related to the predictable Hammett substituent effects. For the natural enantiomers, this unusually small electronic effect on functional reactivity had no perceptible effect on their DNA alkylation selectivity. Similar effects of the C7 cyano substituent on the unnatural enantiomers were observed, and they proved to be 4-10x more effective than the corresponding CBI-based unnatural enantiomers and 4-70x less potent than the CCBI natural enantiomers.

  DOI：

  10.1021/jo9605298

文献信息

• Synthesis of Fluorescence-Labelled Glycosidic Prodrugs Based on the Cytotoxic Antibiotic Duocarmycin
  作者：Lutz F. Tietze、Frank Behrendt、Felix Major、Birgit Krewer、J. Marian von Hof

  DOI：10.1002/ejoc.201000966

  日期：2010.12

  The synthesis of the glycosidic prodrugs (1S)-30a, (1S,10R)-30b and (1S,10R)-32 labelled with different fluorescence dyes at different positions at the aromatic A-ring in 2 is described ; the compounds are structurally based on the cytotoxic antibiotic duocarmycin SA. For binding, the amino compounds (1S)-3a and (1S,10R)-3b were treated with the commercially available succinimides of the dyes 5-SFX

  描述了在2中芳族A环的不同位置用不同荧光染料标记的糖苷前药(1S)-30a、(1S,10R)-30b和(1S,10R)-32的合成；这些化合物在结构上基于细胞毒性抗生素 duocarmycin SA。为了结合，氨基化合物(1S)-3a和(1S，10R)-3b分别用染料5-SFX (29)和D10162 (31)的市售琥珀酰亚胺处理。