| Project/Area Number |
16590022
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
NODE Manabu Kyoto Pharmaceutical University, Faculty of Pharmaceutical Science, Professor, 薬学部, 教授 (60027076)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | (-)-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 / ヒガンバナ科植物 / 遠隔位不斉誘導 / Michael付加 / phenyliodine(iii)bis(trifluoroacetate) |
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| Research Abstract |
(-)-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)>
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