Synthesis of Biologically Active Compounds Using Radical Cyclization Based on New Methodologies

基于新方法的自由基环化合成生物活性化合物

• 批准号: 13470469
• 负责人: ISHIBASHI Hiroyuki
• 金额: $ 8.51万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470469/
• 关键词: radical cyclization; vinyl sulfide; mappicine ketone; mantganese(III) acetate; regiochemistry; (-)-aphanorphine; Erythrina alkaloid; oxidative radical cyclization; メチルチオアミド; アリールラジカル環化反応; アファノルフィン; ハイポエステスタチン; セファロタキシン; エナミド; ラジカル; 環化反応; ア

Radical cyclization was recognized as a valuable tool for the construction of cyclic compounds, and the methods have been widely employed in the field of organic synthesis including natural products synthesis. However, there are many ploblems which required solvation in this useful radical cyclizations. One of them is the controlling regiochemistry. If this problem is solved, the radical cyclization would be highly promising. A new method for generation of radical species is also required. We, therefore, examined several radical cyclizations in more details, and found the following evidences.1)A new method for the synthesis of mappicine ketone, an antiherpesvirus compound, has been developed by using sulfur-directed 5-exo selective aryl radical cyclization. 2)A new method for the, synthesis of an analgesic(-)-aphanorphine has been developed by using sulfur-directed 6-exo selective aryl radical cyclization. 3)5-Endo and 4-exo selectivity in radical cyclization of N-(2-phenylthio and 2-phenyl-1-cyclohexenyl)-α-haloamides have been elucidated. 4)A radical cascade involving a 5-endo cyclization of α-amidoyl radicals has been found. 5)It was found that the use of iodine atom as a leaving group is not recommended for the 5-endo radical cyclization of N-vinylic α-haloamides. 6)A new synthesis of erythrinane skeleton which consisted of treatment of α-(methylthio)acetamides with Mn(OAc)_3 in the presence of Cu(II) was found, and the method was applied to the synthesis of 3-demethoxyerythratidinone, a naturally occurring Erythrina alkaloid.

自由基环化反应被认为是构建环状化合物的重要手段，在包括天然产物在内的有机合成领域得到了广泛的应用。然而，在这些有用的自由基环化反应中，存在许多需要溶剂化的问题。其中之一是控制区域化学。如果这个问题得到解决，自由基环化反应将非常有前途。还需要一种产生自由基物质的新方法。因此，我们对几种自由基环化反应进行了更详细的研究，并发现了以下证据：1）通过硫导向的5-外选择性芳基环化反应，发展了一种合成抗疱疹病毒化合物马匹辛酮的新方法。2）提出了一种新的合成镇痛药（-）-阿法诺啡的方法，即硫导向的6-外选择性芳基环化反应。3)5-本文研究了N-（2-苯硫基和2-苯基-1-环己烯基）-α-卤代酰胺自由基环化反应的内、外选择性。4）发现了α-酰胺基自由基5-内环化的自由基级联反应，5）发现N-乙烯基α-卤代酰胺的5-内环化反应不宜用碘原子作离去基团。6）在Cu（Ⅱ）存在下，通过Mn（OAc）_3与α-（甲硫基）乙酰胺反应，得到了一种新的合成藜芦烷骨架的方法，并将该方法应用于刺桐生物碱3-去甲氧基藜芦酮的合成。

项目成果

近岡志保: "Mn(III)/Cu(II)-Mediated Oxidative Radical Cyclization of a-(Methylthio)-acetamides Leading to Erythrinanes."J.Org.Chem.. 68. 312-318 (2003)

Shiho Chikaoka：“Mn(III)/Cu(II) 介导的α-(甲硫基)-乙酰胺氧化自由基环化生成赤藓烷。”J.Org.Chem.. 68. 312-318 (2003)

Shiho Chikaoka, Atsushi Toyao, Mizuho Qgasawara, Osamu Tamura, Hiroyuki Ishibashi: "Mn(III)/Cu(II)-Mediated Oxidative Radical Cyclization of a-(Methylthio)-acetamides Leading to Erythrinanes."J.Org.Chem.. 68. 312-318 (2003)

Shiho Chikaoka、Atsushi Toyao、Mizuho Qgasawara、Osamu Tamura、Hiroyuki Ishibashi：“Mn(III)/Cu(II) 介导的 α-(甲硫基)-乙酰胺氧化自由基环化生成刺桐烷。”J.Org.Chem..

田村 修: "Synthesis of (-)-Aphanorphione Using Aryl Radical Cyclization"Organic Letters. 3・16. 2427-2429 (2001)

Osamu Tamura：“利用芳基自由基环化合成(-)-Aphanorphione”有机快报3·16（2001）。

石橋弘行: "Synthesis of a Model Compound of Mappicine Ketone Based on Sulfur-Directerd 5-Exo Selective Aryl Radical Cyclization onto Enamides."Tetrahedron Letters. 42・5. 931-933 (2001)

Hiroyuki Ishibashi：“基于硫导向的 5-Exo 选择性芳基环化到四面体字母上的马匹辛酮模型化合物的合成”42・5。

田村 修: "Synthesis of(-)-Aphanorphine Using Aryl Radical Cyclization."Org.Lett.. 3. 2427-2429 (2001)

Osamu Tamura：“使用芳基自由基环化合成 (-)-阿法诺啡。”Org.Lett.. 3. 2427-2429 (2001)