A Total Synthesis of Galanthamine Involving De Novo Construction of the Aromatic C‐Ring. Issue 17 (29th April 2015)

• Record Type: Journal Article
• Authors: Nugent, Jeremy; Matoušová, Eliška; Banwell, Martin G.
• Is Part Of: European journal of organic chemistry. Issue 17(2015)
• Page Start: 3771
• Page End: 3778
• Publication Date: 2015-04-29
• Subjects: Natural products -- Total synthesis -- Alkaloids -- Alder‐ene reactions -- Diels–Alder reactions -- Cycloaddition; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201500365
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: The tetracyclic alkaloid galanthamine is used clinically in a number of countries for the symptomatic treatment of mild to moderate forms of Alzheimer's disease, and this feature coupled with its novel molecular architecture has prompted an extensive focus on its synthesis. The present study reports a new and distinct synthesis of galanthamine wherein the AB‐ring substructure and associated quaternary carbon centre are constructed by using a palladium‐catalyzed intramolecular Alder‐ene reaction. The product of this process is engaged in a Tsuji–Trost‐type reaction to generate a semicyclic diene that participates in a normal‐electron‐demand Diels–Alder reaction to generate, after oxidation of the initially formed adduct, the aromatic C‐ring of the target alkaloid. Modified Bischler–Napieralski chemistry is then deployed to construct the seven‐membered D‐ring and thereby furnishing narwedine, an established precursor to both (+)‐ and (–)‐galanthamine. Abstract : The first synthesis of the alkaloid galanthamine is reported in which the aromatic C‐ring is assembled from non‐aromatic precursors. This was accomplished by a Diels–Alder cycloaddition reaction. The diene used embodies the AB‐ring system (and associated quaternary carbon centre) and was constructed by intramolecular Alder‐ene and Tsuji–Trost‐type chemistries. The D‐ring was closed by a modified Bischler–Napieralski reaction.