Establishment of Highly Selective Radical Cyclization and Application to the Synthesis of Biologically Active Compounds

高选择性自由基环化反应的建立及其在生物活性化合物合成中的应用

• 批准号: 08672419
• 负责人: ISHIBASHI Hiroyuki
• 金额: $ 1.6万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672419/
• 关键词: alkaloid synthesis; asymmetric induction; beta-lactam; lycorane; 1beta-methylcarbapenem; 4-oxo-2-azetidineacetic acid; radical cyclization; thienamycin; テトラヒドロパルマチン; カルバペネム; PS-5; チレニン; レンノキサミン

Bu_3SnH-mediated regio- and stereoselective radical cyclizations of alpha-holo amides have been examined. The results are summarized below.1. The 4-exo radical cyclization of N-vinylic alpha-halo amides, bearing a chiral auxiliary on the nitrogen atom or at the alpha-position of the carbonyl group, was found to proceed with high degree of diastereoselectivy to give optically active beta-lactams. The methods were applied to the synthesis of optically active carbapenem antibiotics such as (+) -PS-5, (+) -thienamycin and 1beta-methylcarbapenem.2. The 5-endo radical cyclization of N- (1-cyclohexenen-1-yl) -alpha-haloacetamides bearing a chiral auxiliary on the nitrogen atom was found to proceed with moderate degree of diastereoselectivy t give optically active octahydroindol-2-ones. The method was applied to the total synthesis of (-) -gamma-lycorane.3. The radical cyclization of N- (2-phenylthio-1-cyclohexenen-1-yl) -alpha-haloacetamies has been examined, and it was found that the course of the cyclizations was atrikingly affected by the reaction temperature employed. Thus, at room temperature, 4-exo cyclization predominated, and at higher temperature (in boiling toluene), 5-endo cyclization predominated.4. The kN-vinyl-2-bromobenzamides or N-vinyl-2- (2-bromophenyl) acetamides bearing a phenylthio group at the terminus of their N-vinylic bond were found to undergo radical cyclization in a 5-exo-trig or in a 6-exo-trig manner effectively to give isoindolone and isoquinolinones, respectively. The methods were applied to the synthesis of some alkaloids such as chilenine, lennoxamine, tetrahydropalmatine and saulatine.5. The N- [o- (2-propenyl) phenyl] -2,2-bis (phenylthio) acetamides were found to undergo radical cyclization in an 8-endo-trig manner to give benzoazocinone derivatives.

本文研究了Bu_3SnH催化的α-全息酰胺的区域和立体选择性自由基环化反应。研究结果总结如下：1.N-乙烯基α-卤代酰胺的4-外自由基环化反应，在氮原子上或在羰基的α位置带有手性助剂，具有很高的非对映选择性，得到光学活性的β-内酰胺类化合物。将该方法应用于光学活性碳青霉烯类抗生素(+)-PS-5、(+)-硫代霉素和1-β-甲基碳青霉烯的合成。N-(1-环己烯-1-基)-α-卤代乙酰胺的N-(1-环己烯-1-基)-α-卤代乙酰胺的5-内基环化反应具有中等程度的非对映选择性，得到光学活性的八氢吲哚-2-酮。将该方法应用于(-)-伽马-石蒜烷的全合成。研究了N-(2-苯硫基-1-环己烯-1-基)-α-卤代乙酰胺的自由基环化反应，发现反应温度对环化过程有很大影响。因此，在室温下，以4-外环化为主，在较高温度下(甲苯沸腾)，以5-内环化为主。在N-乙烯基键末端带有苯硫基的KN-乙烯-2-溴苯甲酰胺或N-乙烯-2-(2-溴苯基)乙酰胺分别以5-外触发或6-外触发方式进行自由基环化，分别得到异吲哚和异喹诺酮。将该方法应用于辣椒碱、来诺沙明、延胡索乙素、苏拉汀等生物碱的合成。N-[O-(2-丙烯基)苯基]-2，2-二(苯硫基)乙酰胺经8-内切自由基环化得到苯并偶氮酮类化合物。

项目成果

石橋弘行: "Effect of Temperature on 5-Endo- and 4-Exo-Trig Radical Cyclizations of N-Vinylic α-Halo Amides." Tetrahedron Lett.39. 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。”39 (1998)。

石橋 弘行: "Sulfur-Controlled 5-Exo Selective Aryl Radical Cyclisation of N-Vinylic 2-Bromobenzamides : Synthesis of Lennoxamine and Chilenine." J.Chem.Soc.,Perkin Trans.1. 817-821 (1997)

Hiroyuki Ishibashi：“N-乙烯基 2-溴苯甲酰胺的硫控制 5-Exo 选择性芳基自由基环化：Lennoxamine 和 Chilenine 的合成”，J.Chem.Soc.，Perkin Trans.1 (1997)。

Ikeda, M. ; Ohtani, S. ; Okada, M. ; Minakuchi, E. ; Sato, T. ; Ishibashi, H.: "5-Endo-Trig Radical Cyclization of 2-Chloro- and 2,2-Bis (phenylthio) -N-methyl-N- (6-phenylcyclohex) -1-en-1-yl) acetamides" Heterocycles. 47. 181-186 (1998)

池田，M.；

石橋 弘行: "Synthesis of 4-Oxo-2-azetidineacetic Acids by Means of Radical Cyclization of N-Vinylic α-Bromo Amides." Tetrahedron. 52. 13867-13880 (1996)

Hiroyuki Ishibashi：“通过 N-乙烯基 α-溴代酰胺的自由基环化合成 4-Oxo-2-氮杂环丁烷乙酸。”52。13867-13880 (1996)

池田 正澄: "Triethylborane-Mediated Atom Transfer Cyclization of 2-Iodo-N-(prop-2-enyl)acetamides and Related Compounds" J.Chem.Soc.,Perkin Trans.1. (印刷中).

Masazumi Ikeda：“2-碘-N-(丙-2-烯基)乙酰胺和相关化合物的三乙基硼烷介导的原子转移环化”J.Chem.Soc.，Perkin Trans.1（出版中）。