Methyl 4-bromo-5-[(2-methylpropan-2-yl)oxycarbonylamino]-7-phenylmethoxy-1-benzofuran-2-carboxylate | 199280-12-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: Methyl 4-bromo-5-[(2-methylpropan-2-yl)oxycarbonylamino]-7-phenylmethoxy-1-benzofuran-2-carboxylate
• CAS: 199280-12-1
• 化学式: C₂₂H₂₂BrNO₆
• 分子量: 476.324
• InChiKey: QOGZTUANCPNJBD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  87
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Methyl 4-bromo-5-[(2-methylpropan-2-yl)oxycarbonylamino]-7-phenylmethoxy-1-benzofuran-2-carboxylate 在 盐酸 、 偶氮二异丁腈 、 三正丁基氢锡 、 sodium hydride 、 碳酸氢钠 作用下， 以 四氢呋喃 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 15.5h， 生成 methyl 3-(chloromethyl)-4-hydroxy-2,3-dihydrobenzo[f]indole-1-carboxylate
  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：

  methyl 7-hydroxy-5-nitro-1-benzofuran-2-carboxylate 在 palladium/alumina N-溴代丁二酰亚胺(NBS) 、 硫酸 、 氢气 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， -60.0~25.0 ℃ 、413.69 kPa 条件下， 反应 49.0h， 生成 Methyl 4-bromo-5-[(2-methylpropan-2-yl)oxycarbonylamino]-7-phenylmethoxy-1-benzofuran-2-carboxylate
  参考文献：
  名称：

  Total Synthesis of Seco (+)- and ent-(−)-Oxaduocarmycin SA:  Construction of the (Chloromethyl)indoline Alkylating Subunit by a Novel Intramolecular Aryl Radical Cyclization onto a Vinyl Chloride

  摘要：

  A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogue of the highly cytotoxic natural product, duocarmycin SA (1), is described. The 13-step synthesis features a novel and efficient intramolecular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolution, utilizing a preparative Chiralpak AD column, provided enantiomerically pure alkylating subunits 14a and 14b which were elaborated to seco-(+) and ent-(-)-oxaduocarmycins, 3a and 3b, respectively. The natural enantiomer 3a was active at pM concentrations and exhibited 7-50-fold higher potentcy than its enantiomer 3b in in vitro cytotoxicity assays.

  DOI：

  10.1021/jo971880b

文献信息

• 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
  作者：Dale L. Boger、Robert M. Garbaccio、Qing Jin

  DOI：10.1021/jo971686p

  日期：1997.12.1

  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.
• Total Synthesis of Seco (+)- and <i>ent</i>-(−)-Oxaduocarmycin SA:  Construction of the (Chloromethyl)indoline Alkylating Subunit by a Novel Intramolecular Aryl Radical Cyclization onto a Vinyl Chloride
  作者：Vinod F. Patel、Sherri L. Andis、Julia K. Enkema、David A. Johnson、Joseph H. Kennedy、Fariborz Mohamadi、Richard M. Schultz、Daniel J. Soose、Michael M. Spees

  DOI：10.1021/jo971880b

  日期：1997.12.1

  A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogue of the highly cytotoxic natural product, duocarmycin SA (1), is described. The 13-step synthesis features a novel and efficient intramolecular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolution, utilizing a preparative Chiralpak AD column, provided enantiomerically pure alkylating subunits 14a and 14b which were elaborated to seco-(+) and ent-(-)-oxaduocarmycins, 3a and 3b, respectively. The natural enantiomer 3a was active at pM concentrations and exhibited 7-50-fold higher potentcy than its enantiomer 3b in in vitro cytotoxicity assays.