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。

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590022/
• 关键词: (-)-galanthamine; remote asymmetric induction; norbelladine type compound; oxidative phenol coupling; phenyliodine(III) bis(trifluoroacetate); Amaryllidaceae alkaloids; ガランタミン; アルツハイマー治療薬; 酸化的フェノールカップリング; 不斉全合成; アルツハイマー病治療薬; コリンエステラーゼ阻害活性; ヒガン

(-)-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)>

(-)-加兰他敏是石蒜科的一种生物碱，已被评估为治疗阿尔茨海默病的潜在药物。我们已经通过以下方法实现了 (±)-加兰他敏和 (±)-narwedine 的有效全合成。含连苯三酚部分的降颠茄定型化合物使用苯基碘(III)双(三氟乙酸酯)的分子内氧化苯酚偶联反应(PIFA)作为关键反应。^<1)>在上述合成方法的基础上，我们计划以光学活性氨基酸为手性助剂，不对称合成(-)-加兰他敏，即具有连苯三酚型降贝拉定。以D-苯丙氨酸作为偶联反应的前体，通过手性咪唑啉酮衍生物与苯酚的氧化偶联反应制备了手性咪唑啉酮环。 PIFA 和随后用三氯化硼对连苯三酚部分中受保护的羟基进行脱保护，通过苯酚氧原子与螺二烯酮部分的分子内迈克尔加成得到环醚。在上述迈克尔加成反应中，通过远程不对称诱导非对映选择性地产生了两个手性中心。基于手性咪唑啉酮环对七元环的构象限制，将环醚有效地转化为环醚。 (-)-加兰他敏。^<2)> 此外，还研究了 PIFA 介导的分子内偶联反应在合成其他石蒜科生物碱中的应用，研究了四种 crinane 类型的生物碱（sicline、crinine、epicrinine 和 oxocrinine）。还通过偶联反应和二烯酮-苯酚制备了高产率的黄黄素。重新排列。^<3)>