N-(tert-Butyloxycarbonyl)-3-iodo-4-(methoxymethoxy)-2-naphthylamine | 198708-96-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(tert-Butyloxycarbonyl)-3-iodo-4-(methoxymethoxy)-2-naphthylamine
• 英文别名: tert-butyl N-[3-iodo-4-(methoxymethoxy)naphthalen-2-yl]carbamate
• CAS: 198708-96-2
• 化学式: C₁₇H₂₀INO₄
• 分子量: 429.255
• InChiKey: KWAFXJTULIKDGH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(tert-Butyloxycarbonyl)-3-iodo-4-(methoxymethoxy)-2-naphthylamine 在 盐酸 、 四氯化碳 、 三正丁基氢锡 、 sodium hydride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 溶剂黄146 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 、 苯 为溶剂， 反应 9.25h， 生成 7-[7-(9-Oxo-1a,2-dihydro-1H,9H-3-aza-cyclopropa[1,5]cyclopenta[1,2b]naphthalene-3-carbonyl)-1,6-dihydro-2H-pyrrolo[3,2-e]indole-3-carbonyl]-1,6-dihydro-2H-pyrrolo[3,2-e]indole-3-carboxylic acid amide
  参考文献：
  名称：

  Synthesis and Evaluation of CC-1065 and Duocarmycin Analogues Incorporating the Iso-CI and Iso-CBI Alkylation Subunits:  Impact of Relocation of the C-4 Carbonyl

  摘要：

  The synthesis of 2-(tert-Butyloxycarbonyl)-1, 2, 9, 9a-tetrahydrocyclopropa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-Butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2, 3-dihydroindole (19, seco-N-BOC-iso-CI) containing an isomeric structural modification in the CC-1065 and duocarmycin alkylation subunits and their incorporation into analogues of the natural products are detailed. The approach was based on a directed ortho metalation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization. The evaluation of the iso-CBI-based agents revealed a significant stability comparable to that of CC-1065 and duocarmycin A, but that it is more reactive than duocarmycin SA (6 - 7x) or the direct comparison CBI-based agents (5x) for which X-ray structure comparisons served to establish the basis for their inherent reaction regioselectivity and reactivity. Resolution and synthesis of a full set of natural product analogues and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogues, even with the relocation of the C-4 carbonyl and the most substantial structural modifications to the alkylation subunit to date, reacted at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alkylation site. Confirmation that the DNA alkylation reaction is derived from adenine N3 addition to the least substituted carbon of the activated cyclopropane, and its quantitation (95%) was established by isolation and characterization of the depurination adenine N3 adduct. Consistent with past studies and despite the deep-seated structural change in the alkylation subunit, the agents were found to exhibit potent cytotoxic activity that correlates with their inherent reactivity.

  DOI：

  10.1021/jo971686p
• 作为产物：
  描述：

  N-(tert-Butyloxycarbonyl)-4-(methoxymethoxy)-2-naphthylamine 在 正丁基锂 、 1-氯-2-碘乙烷 、 四甲基乙二胺 作用下， 生成 N-(tert-Butyloxycarbonyl)-3-iodo-4-(methoxymethoxy)-2-naphthylamine
  参考文献：
  名称：

  Synthesis and Evaluation of CC-1065 and Duocarmycin Analogues Incorporating the Iso-CI and Iso-CBI Alkylation Subunits:  Impact of Relocation of the C-4 Carbonyl

  摘要：

  The synthesis of 2-(tert-Butyloxycarbonyl)-1, 2, 9, 9a-tetrahydrocyclopropa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-Butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2, 3-dihydroindole (19, seco-N-BOC-iso-CI) containing an isomeric structural modification in the CC-1065 and duocarmycin alkylation subunits and their incorporation into analogues of the natural products are detailed. The approach was based on a directed ortho metalation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization. The evaluation of the iso-CBI-based agents revealed a significant stability comparable to that of CC-1065 and duocarmycin A, but that it is more reactive than duocarmycin SA (6 - 7x) or the direct comparison CBI-based agents (5x) for which X-ray structure comparisons served to establish the basis for their inherent reaction regioselectivity and reactivity. Resolution and synthesis of a full set of natural product analogues and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogues, even with the relocation of the C-4 carbonyl and the most substantial structural modifications to the alkylation subunit to date, reacted at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alkylation site. Confirmation that the DNA alkylation reaction is derived from adenine N3 addition to the least substituted carbon of the activated cyclopropane, and its quantitation (95%) was established by isolation and characterization of the depurination adenine N3 adduct. Consistent with past studies and despite the deep-seated structural change in the alkylation subunit, the agents were found to exhibit potent cytotoxic activity that correlates with their inherent reactivity.

  DOI：

  10.1021/jo971686p

文献信息

• ISO-CBI and ISO-CI analogs of CC-1065 and the duocarmycins
  申请人：The Scripps Research Institute

  公开号：US06262271B1

  公开（公告）日：2001-07-17

  A series of bioactive analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI (6 and 7) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhanced reactivity.

  合成了一系列生物活性类似物(+)-CC-1065 (1)和duocarmycins 2和3。这些生物活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些生物活性类似物保持其DNA选择性并显示出增强的反应性。
• Synthesis of CC-1065 and duocarmycin analogs via intramolecular aryl radical cyclization of a tethered vinyl chloride
  作者：Dale L. Boger、Christopher W. Boyce、Robert M. Garbaccio、Mark Searcey

  DOI：10.1016/s0040-4039(98)00232-9

  日期：1998.4

  The 5-exo-trig radical cyclization of an aryl halide onto a tethered vinyl chloride produces the 3-chloromethyl dihydroindole precursors for CC-1065 and duocarmycin analogs with chlorine installed as a suitable leaving group for subsequent cyclopropane spirocyclization. The generality of this approach was examined in the context of six CC-1065 and duocarmycin analogs previously synthesized in this

  芳基卤化物在束缚的氯乙烯上的5- exo - trig自由基环化反应生成CC-1065和Duocarmycin类似物的3-氯甲基二氢吲哚前体，并安装了氯作为随后的环丙烷螺环化反应的合适离去基团。该方法的普遍性已在该实验室中先前合成的六种CC-1065和杜卡霉素类似物的背景下进行了研究。
• iso-CBI and iso-CI analogs of CC-1065 duocarmycins
  申请人：The Scripps Research Institute

  公开号：US20020049335A1

  公开（公告）日：2002-04-25

  A series of bioactive analogs of (+)-CC-1065 ( 1 ) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI ( 6 and 7 ) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhance reactivity.

  合成了一系列活性类似物，包括(+)-CC-1065 (1)和duocarmycins2和3。这些活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些活性类似物保持其DNA选择性并显示增强的反应性。
• iso-CBI AND iso-CI ANALOGS OF CC-1065 AND THE DUOCARMYCINS
  申请人：The Scripps Research Institute

  公开号：EP1042285A1

  公开（公告）日：2000-10-11
• EP1042285A4
  申请人：——

  公开号：EP1042285A4

  公开（公告）日：2002-11-20