Study on Effective Asymmetric Total Synthesis of Gallanthamine, a Drug for Alzheimer's disease.

阿尔茨海默病药物加兰他敏的有效不对称全合成研究。

基本信息

批准号：
16590022
负责人：
NODE Manabu
金额：
$ 2.24万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

(-)-Galanthamine, an alkaloid of the Amaryllidaceae family, has been evaluated as a potential agent for the treatment of Alzheimer's disease. We have already accomplished an efficient total synthesis of (±)-galanthamine and (±)-narwedine by means of intramolecular oxidative phenol coupling reaction of norbelladine type compound containing pyrogallol moiety using phenyliodine(III) bis(trifluoroacetate) (PIFA) as a key reaction.^<1)>On the basis of the above synthetic method, we planned an asymmetric synthesis of (-)-galanthamine using optically active amino acid as a chiral auxiliary. Namely, pyrogallol-type norbelladine having chiral imidazolidinone ring was prepared from D-phenylalanine as a precursor of the coupling reaction. The oxidative phenol coupling reaction of the chiral imidazolidinone derivative with PIFA and subsequent deprotection of protected hydroxyl groups in pyrogallol moiety with boron trichloride gave the cyclic ether via intramolecular Michael addition of phenol oxygen atom to spiro-dienone moiety. In the above Michael addition reaction, two chiral centers were diastereoselectively created by the remote asymmetric induction based on conformational restriction of seven membered ring by the chiral imidazolidinone ring. The cyclic ether was effectively converted into (-)-galanthamine.^<2)> In addition, the PIFA-mediated intramolecular coupling reaction was investigated as its application for the synthesis of other Amarylidaceae alkaloids. Four crinane type of alkaloids (sicline, crinine, epicrinine, and oxocrinine) were synthesized by the coupling reaction in high yields. Buflavine was also prepared by the use of the coupling reaction followed by dienone-phenol rearrangement.^<3)>

（ - ） - 果蝇科的生物碱甘烷胺已被评估为治疗阿尔茨海默氏病的潜在药物。我们已经通过（±） - 甘丙酰胺和（±） - 纳维丁实现了通过含有苯甲酸酯型含丙糖果部分的Norbelladine型化合物的氧化物内氧化物苯酚酚偶联反应的（±） - 纳维丁的有效总合成。方法，我们计划使用光学活性氨基酸作为手性辅助的（ - ） - 葡萄干胺的不对称合成。也就是说，从D-苯基丙氨酸作为偶联反应的前体制备了手性咪唑替奈酮环的丙糖醇型诺贝拉丁。手性咪唑啉酮衍生物与PIFA的氧化苯酚偶联反应以及随后在邻苯二酚部分中脱离受保护的羟基与三氯化硼的脱身性脱脱骨，通过分子内迈克尔添加了酚氧气对Spiro-dienone Moiter的苯酚氧气中的添加。在上述迈克尔加法反应中，基于手性咪唑替诺酮环对七个成员环的构象限制，由远程不对称诱导产生了两个手性中心。循环醚有效地转化为（ - ） - 甘氨酸。通过高产量以偶联反应合成了四种红烷类型的生物碱（Sicline，Crinine，Epicrinine和Oxocrinine）。 Buflavine还通过使用偶联反应，然后是二烯 - 苯酚重排。^<3）>