Synthetic Studies on Martinellines, Novel G-protein Linked Receptor Antagonist

新型G蛋白连接受体拮抗剂马丁内林的合成研究

• 批准号: 12672048
• 负责人: HARA Osamu
• 金额: $ 0.77万
• 依托单位: CHIBA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672048/
• 关键词: martinelline; martinellic acid; ring closing metathesis; regioselectiue crotylation; asymmetric allylic amination; Michael-Aldol reaction; 分子内アリル位置換反応; cross metathesis反応; シリコン架橋閉環メタセシス反応

Martinelline and martinellic acid were isolated from tropical plant Martinella iquitosensis by Witherrup and coworkers. These alkaloids were the first naturally occurring nonpeptide bradykinin receptor antagonists and also the first naturally occurring pyrrolo[3,2-c]quinoline system. Interests on the unique structure of these as well as its biological activity led us to a total synthesis of martinelline and martinellic acid. The key step in our synthesis of these alkaloids is the asymmetric allylic substitution of aniline derivative by the combination of Pd (dba)_2 and 9-PBN. Basic experimental results showed that 2-vinyl-tetrahydroquinoline was provided with high enantioselectivity (92 %ee). For the synthesis of martinellines by this methodology, the precursor of cyclization product was prepared from hydroxyanthranilic acid by two methods. One was the ring closing metathesis reaction tethered with silicon atom and the other method was the regioselective crotylation reaction mediated with SnCl_4. Obtained tetrahydroquinoline was converted to the desired pyrroloquinoline ring with reductive amination reaction after introduction of cyanoethyl group at C-3. Vinyl group at C-2 was also converted to the desired cyanoethyl residue in general methods. And we also developed a new synthetic method for the preparation of hydroquinoline derivatives with Michael-Aldol reaction under the phase-transfer condition. This method is very useful method for not only the synthesis of martinellines but also biologically active quinoline derivatives. We achieved the synthesis of common intermediate of martinellines.

由Witherrup等人从热带植物马丁内斯中分离得到马丁内林和马丁酸。这些生物碱是第一个天然存在的非肽缓激肽受体拮抗剂，也是第一个自然存在的吡咯并[3，2-c]喹啉体系。对这些化合物的独特结构和生物活性的兴趣使我们合成了马丁烯和马丁酸。合成这些生物碱的关键步骤是Pd(Dba)_2与9-PBN的不对称烯丙基取代苯胺衍生物。基本实验结果表明，2-乙烯基四氢喹啉具有较高的对映选择性(ee=92%)。以羟基邻氨基苯甲酸为原料，通过两种方法制备了环化产物的前体。一种是硅原子束缚的闭环歧化反应，另一种是四氯化锡催化的区域选择性巴豆化反应。在C-3位引入氰乙基后，四氢喹啉通过还原胺化反应转化为所需的吡咯喹啉环。在一般方法中，C-2上的乙烯基团也可转化为所需的氰乙基残基。开发了一种在相转移条件下利用Michael-Aldol反应合成氢喹啉衍生物的新方法。该方法不仅对马丁内酯的合成，而且对生物活性喹啉类化合物的合成都是非常有用的方法。实现了马丁内酯常见中间体的合成。

项目成果

濱田康正, 国宗壱与, 原脩: "Asymmetric Synthesis of Tetrahydroquinoline Derivative, a Building Block of Martinellines, via Intramolecular Allylic Amination using 9-PBN"Heterocycles. 56巻. 97-100 (2002)

Yasumasa Hamada、Ichiyo Kunimune、Osamu Hara：“使用 9-PBN 进行分子内烯丙基胺化，四氢喹啉衍生物的不对称合成”，第 56 卷，97-100 (2002)。

Yasumasa Hamada, Iyo Kunimune, Osamu Hara: "Asymmetric synthesis of Tetrahydroquinoline Derivative, a Building Block of Martinellines, via Intramolecular Allylic Amination Using 9-PBN"Heterocycles. Vol. 56. 97-100 (2002)

Yasumasa Hamada、Iyo Kunimune、Osamu Hara：“使用 9-PBN 进行分子内烯丙基胺化，不对称合成四氢喹啉衍生物（Martinellines 的组成部分）”杂环。