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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)>

(-)-加兰他明是石蒜科生物碱，已被评估为治疗阿尔茨海默病的潜在药物。以苯碘(III)双(三氟乙酸酯)(PIFA)为关键反应，通过去甲肾上腺素类化合物的分子内氧化苯酚偶联反应，实现了(±)-加兰他明和(±)-那维汀的高效全合成。在上述合成方法的基础上，我们计划了以光学活性氨基酸为手性助剂的(-)-加兰他明的不对称合成。也就是说，以D-苯丙氨酸为偶联反应的前体，合成了具有手性咪唑烷酮环的邻苯三酚类去甲肾上腺素。手性咪唑烷酮类化合物与PIFA发生氧化偶联反应，然后用三氯化硼去除邻苯三酚中受保护的羟基，通过分子内Michael加成反应将苯酚氧原子加成到螺二烯酮部分，得到了环醚。在上述Michael加成反应中，手性咪唑烷酮环对七元环的构象限制通过远程不对称诱导选择性地生成了两个手性中心。该环醚可有效地转化为(-)-加兰他明。此外，PIFA介导的分子内偶联反应也被用于合成其他石蒜科生物碱。通过偶联反应，高产率地合成了四种金刚烷型生物碱(马钱子碱、马钱子碱、表麦角碱和奥克林碱)。还利用偶联反应和二烯酮-苯酚重排反应合成了布黄素。