34 The Total Syntheses of Amaryllidaceae Alkaloids Using Phenolic Coupling Reaction
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(-)-Galanthamine (1), an alkaloid of the Amaryllidaceae family, has been evaluated as a potent agent for the treatment of Alzheimer's disease. Because of the scarcity of natural supply, several syntheses of galanthamine have been reported using biomimetic phenolic oxidative coupling of a norbelladine derivative and recently via an asymmetric Heck reaction. Despite of these efforts, the yield of the pivotal coupling reaction in these syntheses still remains only moderate (〜50%). We accomplished an efficient total synthesis of (±)-galanthamine through the improved phenolic oxidative coupling reaction of norbelladine-type compound 1 having pyrogallol moiety. Namely, the coupling reaction of 1e using phenyliodine(III)bis(trifluoroacetate) (PIFA) gave the spiro-dienone 2e in high yield (85%), which was converted into (±)-galanthamine and (±)-narwedine. On the basis of the above synthetic method, we planned an asymmetric synthesis of (±)-galanthamine using optically active amino acid as a chiral auxiliary. Acidic cyclization of a D-phenylalanine derivative 11a with a benzaldehyde derivative 8a gave the imidazolidinone derivative 12a as a single diastereomer. The oxidative coupling of 12a with PIFA and subsequent debenzylation with boron trichloride gave the cyclic ether 13. In the above reaction, two chiral centers were created by the remote asymmetric induction based on conformational restriction of the chiral imidazolidinone ring. The cyclic ether 13 was effectively converted into (-)-galanthamine. Buflavine, isolated from boophane flava (Amaryllidaceae), has been shown to exhibit strong α-adrenolytic and anti-serotonine activities. We accomplished a total synthesis of buflavine through the above coupling reaction of norbelladine derivative 16 and a dienone-phenol rearrangement of the spiro-dienone 17. We also achieved a total synthesis of (±)-oxocrinine, isolated from Crinum americanum (Amaryllidaceae), through the above coupling reaction of norbelladine derivative 20 and the Michael addition of amino group to the dienone moiety of 21.
