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

（-）-加兰他敏，一种amaryllidfamily的生物碱，已被评估为治疗阿尔茨海默病的潜在药物。我们已经以苯基吡啶（III）双（三氟乙酸酯）（PIFA）为关键反应，通过含邻苯三酚片段的去苯拉定型化合物的分子内氧化苯酚偶联反应，实现了（±）-加兰他敏和（±）-萘啶的高效全合成。在上述合成方法的基础上，我们计划以旋光性氨基酸为手性助剂不对称合成(-)-加兰他明。即以d -苯丙氨酸为偶联反应前体，制得具有手性咪唑烷酮环的邻苯五酚型去贝拉定。手性咪唑烷酮衍生物与PIFA发生酚氧化偶联反应，邻苯三酚部分被保护羟基与三氯化硼脱保护，通过苯酚氧原子在螺二烯酮部分的分子内Michael加成得到环醚。在上述Michael加成反应中，基于手性咪唑烷酮环对七元环构象的限制，通过远不对称诱导，非对映选择性地产生了两个手性中心。环醚有效地转化为(-)-加兰他明。此外，还研究了pifa介导的分子内偶联反应及其在其他漆木科生物碱合成中的应用。通过偶联反应，高收率合成了四种碱类生物碱（sicine、criinine、epicrinine和oxocrinine）。二烯酮-苯酚重排偶联反应制备黄酮类化合物

(-)-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)>