Synthesis of Pharmacologically Active Natural Products using Radical Translocation/cyclization Reactions

利用自由基易位/环化反应合成具有药理活性的天然产物

• 批准号: 11672125
• 负责人: IKEDA Masazumi
• 金额: $ 2.24万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672125/
• 关键词: radical translocation; cyclization; α-acylamino radical; aryl radical; 6-exo-dig; tetrahydroisoquinoline; 9-azabicyclo [ 3.3.1] nonane; 2-azabicyclo [3.2.1] octane; euphococcinine; benzocycloocten-5,9-imine; 6-exo-dig; 5-exo-dig

The scope and limitations of tributyltin hydride (Bu_3SnH)-mediated radical translocation/cyclization reactions and an application to the synthesis of pharmacologically active natural products have been investigated. The results obtained were as follows :(1) Bu_3SnH-mediated radical translocation/cyclization reactions of methyl 1-(o-iodobenzoyl)-2-[4-(trimethylsilyl) but-3-ynyl]-piperi-dine-2-carboxylate and 1-(o-iodobenzoyl)-2-methyl-2-[4-(trimethyl-silyl)but-3-ynyl] piperidine-2-carboxylate proceeded in a regio-selective 6-exo-dig manner to give 9-azabicyclo [3.3.1] nonanes in high yield as a 1 : 1 diastereomeric mixture in both cases. 1-(o-Iodobenzoyl)-2-[4-(trimethylsilyl) but-3-ynyl] piperidine also afforded the 9-azabicyclo [3.3.1] nonane (65%), along with the hexahydropyrido [2, 1-a] isoindolone derivative (23%). Conversion of the 9-azabicyclo [3.3.1] nonane to (±)-euphococcinine was also examined.(2) The reaction of 1-(o-iodobenzoyl)-4-[3-(trimethylsilyl) prop-2-ynyl] piperidine afforded the isomeric 2-azabicyclo [3.2.1] octanes in 34 and 51% yield, along with a trace amount of the reduction product. On the other hand 1-(o-iodobenzoyl)-4-[4-(trimethyl-silyl) but-3-ynyl] piperidine proceeded more slowly to give the 2-azabicyclo [3.3.1] nonane (morphan) in 20% yield as a diastereomeric mixture. In the latter case the reduction product was obtained as a major product in 75% yield.(3) Both 1-[3-(trimethylsilyl) prop-2-ynyl]-and 1-[4-(trimethyl-silyl) but-3-ynyl]-2-(o-iodobenzoyl)-1, 2, 3, 4-tetrahydroiso-quinolines, upon treatment with Bu_3SnH, underwent smoothly either a 5-exo-dig or 6-exo-dig cyclization to give the isomeric 6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5, 8-imines (95%) and 5, 6, 7, 8, 9, 10-hexahydrobenzocycloocten-5, 9-imines (65%), respectively.

研究了氢化三丁基锡（Bu_3SnH）介导的自由基移位/环化反应的范围和局限性，以及在合成具有药理活性的天然产物中的应用。结果表明：(1)bu_3snh介导的1-（邻碘苯甲酰基）-2-[4-（三甲基硅基）- 3-炔基]-哌啶-2-羧酸甲酯和1-（邻碘苯甲酰基）-2-甲基-2-[4-（三甲基硅基）- 3-炔基]哌啶-2-羧酸甲酯自由基转位/环化反应均以区域选择性6-外显方式进行，以1:1非对映体混合物的形式高产出9-氮杂环[3.3.1]壬烷。1-（o-碘苯甲酰）-2-[4-（三甲基硅基）- 3-炔基]哌啶也产生了9-氮杂环[3.3.1]壬烷（65%），以及六氢吡啶[2,1 -a]异吲哚酮衍生物（23%）。还研究了9-氮杂环[3.3.1]壬烷转化为（±）-膦球菌碱。(2) 1-（o-碘苯甲酰基）-4-[3-（三甲基硅基）丙-2-炔基]哌啶反应得到2-氮杂环[3.2.1]辛烷异构体，产率分别为34%和51%，并有微量还原产物。另一方面，1-（邻碘苯甲酰基）-4-[4-（三甲基硅基）- 3-炔基]哌啶反应较慢，以20%的收率生成2-氮杂环[3.3.1]壬烷（morphan）的非对映体混合物。在后一种情况下，还原产物以75%的收率作为主要产品获得。（3) 1-[3-（三甲基硅基）- 2-炔基]和1-[4-（三甲基硅基）- 3-炔基]-2-（邻碘苯甲酰）- 1,2,3,4 -四氢苯甲酰）-1 - 2,3,4 -四氢异喹啉经Bu_3SnH处理后，顺利进行5-外环或6-外环环化，分别得到6,7,8,9 -四氢- 5h -苯并环庚烯- 5,8 -亚胺（95%）和5,6,7,8,9,10 -六氢苯并环庚烯- 5,9 -亚胺（65%）异构体。

项目成果

池田正澄: "Synthesis of bridged benzoazabicyclic compounds using radical translocation /cyclization reactions of 1-alkynyl-2-(ο-idobenzoyl) tetrahydroisoquinolines"Heterocycles. 52-2. 571-574 (2000)

Masazumi Ikeda：“使用 1-炔基-2-（邻基苯甲酰基）四氢异喹啉的自由基转位/环化反应合成桥联苯并氮杂双环化合物”杂环 52-2（2000）。

Tatsunori Sato, Kazuya Okamoto, Yuko Nakano, Jun'ichi Uenishi, and Masazumi Ikeda: "Regioselective synthesis of bridged azabicyclic compounds using radical translocation/cyclization reactions of 4-alkynyl-1-(o-iodobenzoyl)-piperidines"Heterocycles. 54-2.

Tatsunori Sato、Kazuya Okamoto、Yuko Nakano、Junichi Uenishi 和 Masazumi Ikeda：“利用 4-炔基-1-(邻碘苯甲酰基)-哌啶的自由基易位/环化反应进行桥接氮杂双环化合物的区域选择性合成”杂环。

池田正澄: "Synthesis of bridged benzoazabicyclic compounds using radical translocation/cyclization reactions of 1-alkynyl-2-(o-iodobenzoyl) tetrahydroisoquinolines"Heterocycles. 52. 571-574 (2000)

Masazumi Ikeda：“利用 1-炔基-2-(邻碘苯甲酰基)四氢异喹啉的自由基易位/环化反应合成桥联苯并氮杂双环化合物”杂环 52. 571-574 (2000)。

Serry A.A.El Bialy, Shinji Ohtani, Tatsunori Sato, and Masazumi Ikeda: "5-Endo-trig radical cyclization of N-benzyl-2-halo-N-(6-oxo-1-cyclohexen-1-yl) acetamides"Heterocycles. 54-2. 1021-1025 (2001)

Serry A.A.El Bialy、Shinji Ohtani、Tatsunori Sato 和 Masazumi Ikeda：“N-benzyl-2-halo-N-(6-oxo-1-cyclohexen-1-yl) acetamides 的 5-Endo-trig 自由基环化”杂环

池田正澄: "5-Endo-trig radical cyclization of N-benzyl-2-halo-N-(6-oxo-1-cyclohexen-1-yl) acetamides"Heterocycles. 54. 1021-1025 (2001)

Masazumi Ikeda：“N-苄基-2-卤代-N-(6-氧代-1-环己烯-1-基)乙酰胺的 5-Endo-trig 自由基环化”杂环。 54. 1021-1025 (2001)