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

马蒂尼林和马蒂尼酸是由Witherdalam及其同事从热带植物Martinella iquitosensis中分离得到的。这些生物碱是第一个天然存在的非肽类缓激肽受体拮抗剂，也是第一个天然存在的吡咯并[3，2-c]喹啉系统。对这些化合物的独特结构及其生物活性的兴趣促使我们全合成了martinelline和martinellic acid。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反应。基础实验结果表明，2-乙烯基四氢喹啉具有较高的对映选择性（92%ee）。为了用这种方法合成马汀林，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。一种是以硅原子为键的闭环复分解反应，另一种是以SnCl_4为媒介的区域选择性巴豆酰化反应。在C-3位引入氰乙基后，通过还原胺化反应将得到的四氢喹啉转化为所需的吡咯并喹啉环。在一般方法中，C-2处的乙烯基也被转化为所需的氰乙基残基。并发展了一种在相转移条件下利用Michael-Aldol反应合成氢化喹啉衍生物的新方法。该方法不仅对马汀林类化合物的合成，而且对具有生物活性的喹啉衍生物的合成都是非常有用的。实现了马汀类药物常用中间体的合成。

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.