Mechanistic Studies and Synthetic Applications of 5-Endo Radical Cyclization

5-Endo自由基环化的机理研究及合成应用

• 批准号: 09672176
• 负责人: IKEDA Masazumi
• 金额: $ 1.79万
• 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: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672176/
• 关键词: radical cyclization; alkaloid; regioselectivity; asymmetric induction; temperature effect; octahydroindolone; (-)-gamma-lycorane; (*)-pancracine; ラジカル環化反

Mechanistic aspects in the 5-endo radical cyclization of N-vinylic alpha-halo amides and its application to the synthesis of biologically active alkaloids were investigated, The results obtained were as follows :1, The radical cyclization of N-benzyl-2,2,2-trichloro-N-[2-(phenylthio) cyclohex-1-en-1-yl] acetamide in boiling toluene gave the 5-e.ndo-trig cyclization product, whereas, at room temperature, it gave the 4-exo-trig cyclization product. The results may be explained in terms of the reversibility of the 4-exo cyclization.2, The regioselectivity in Bu_3SnH-mediated radical cyclizations (4-exo-trig vs 5-endo-trig) of a range of 2-halo-N-(3,4-dihydro-2-naphthyl)acetamides has been examined from the standpoint of the effects of substituents on the radical center and on the nitrogenatom as well as the reaction temperature. When the substituent on the radical center is a hydrogen or chlorine atom, the 4-exo-trig cyclization (the beta-lactam formation) is favored in boiling toluene, w … More hile the radical stabilizing substituents such as alkyl, phenyl, and phenylthio groups bring about the 5-endo-trig cyclization (the gamma-lactam formation) predominantly or exclusiyely. In boiling benzene, however, the predominant formation of the beta-lactams is observed for the methyl substituent, On the other hand, no remarkable difference in the product distributions between the methyl and benzyl substituents on the nitrogen atom is observed. These results are discussed in terms of kinetic or thermodynamic considerations.3, The radical cyclization of 2-iodo-N-[(S)-1-phenylethyl]-N-(6-oxocyclohex-1-en-1-yl)acetamide proceeded in a 5-endo-trig manner with moderate diastereoselectivity to give the (3aS,7aR)-octahydroindole-2,7-dione as the major product, which was converted into (-)-gamma-lycorane.4, The radical cyclization of N-(cyclohex-1-en-1-yl)-N-(p-methoxybenzyl) -2- (3, 4-methylenedioxyphenyl) -2- (phenylthio) acetamide gave (3R*, 3aS*, 7aS*) -3-aryloctahydroindol-2-one, which was transformed into the key intermediate for the synthesis of (*)-pancracine. Less

研究了N-乙烯基α-卤代酰胺5-内基环化反应的机理及其在生物活性生物碱合成中的应用，结果如下：1、N-苄基-2，2，2-三氯-N-[2-(苯硫基)环己基-1-烯-1-基]乙酰胺在沸腾甲苯中的自由基环化反应生成5-乙基-α-卤代环化产物，而在室温下生成4-外触发环化产物。结果可以用4-外环化的可逆性来解释。2.从取代基对自由基中心和氮原子的影响以及反应温度的角度考察了2-卤代-N-(3，4-二氢-2-萘基)乙酰胺在Bu_3SnH介导的自由基环化反应(4-外三环与5-内三环)中的区域选择性。当自由基中心的取代基是氢原子或氯原子时，沸腾甲苯w…有利于4-外三角环化(β-内酰胺的形成)。而烷基、苯基和苯硫基等自由基稳定的取代基主要或排他性地引起5-内切环化(伽马-内酰胺的形成)。而在沸腾苯中，甲基取代基以β-内酰胺为主，而氮原子上的甲基取代基和苄基取代基之间的产物分布没有显著差异。这些结果从动力学或热力学的角度进行了讨论。3，2-iodo-N-[(S)-1-phenylethyl]-N-(6-oxocyclohex-1-en-1-yl)acetamide的自由基环化反应以5-内触发的方式进行，具有中等的非对映选择性，得到主要产物(3AS，7AR)-八氢吲哚-2，7-二酮，它被转化为(-)-伽马-石蒜烷。4-亚甲基二氧基苯基-2-(苯硫基)乙酰胺得到(3R*，3AS*，7AS*)-3-芳基二氢吲哚-2-酮，转化为合成(*)-潘克拉辛的关键中间体。较少

项目成果

池田正澄: "5-Endo-trig radical cyclization of 2-chloro-and 2,2-bis(pjhenylthio)-N-methy-N-(6-phenylcyclohex-l-en-l-yl)acetamides" Heterocycles. 47・1. 181-186 (1998)

Masazumi Ikeda：“2-氯-和2,2-双(pjhenylthio)-N-甲基-N-(6-苯基环己-1-en-1-基)乙酰胺的5-Endo-trig自由基环化”杂环47。・1。181-186（1998）

池田正澄: "Formal synthesis of (±)-pancracine using stereoselective radical cyclization of N-(2-cyclohexenyl)-α-aryl-α-(phenylthio)acetamide." Synlett. -11. 1246-1248 (1998)

Masumi Ikeda：“利用 N-(2-环己烯基)-α-芳基-α-(苯硫基)乙酰胺的立体选择性自由基环化来正式合成 (±)-pancracine”，Synlett 1246-1248。

石橋弘行: "Effect of temperature on 5-endo-and 4-exo-trig radical cyclizations of N-vinylic α-halo amides" Tetrahedron Letters. 39・1/2. 75-78 (1998)

Hiroyuki Ishibashi：“温度对 N-乙烯基 α-卤代酰胺的 5-endo-和 4-exo-trig 自由基环化的影响”Tetrahedron Letters 39・1/2 (1998)。

池田 正澄: "5-Endo-trig radical cyclization of 2-chloro-and 2, 2-bis-(phenylthio)-N-methyl-N-(6-phenylcyclohex-l-en-l-yl)acetamides." Heterocycles. 47. 181-186 (1998)

Masazumi Ikeda：“2-氯-和2, 2-双-(苯硫基)-N-甲基-N-(6-苯基环己-1-en-1-基)乙酰胺杂环的5-Endo-trig自由基环化。” . 47. 181-186 (1998)

池田 正澄: "Formal synthesis of (±)-pancracine using stereoselective radical cyclization of N-(2-cyclohexenyl)-α-aryl-α-(phenylthio)acetamide." Synlett. -11. 1246-1248 (1998)

Masumi Ikeda：“利用 N-(2-环己烯基)-α-芳基-α-(苯硫基)乙酰胺的立体选择性自由基环化来正式合成 (±)-pancracine”，Synlett 1246-1248。