An Eleven‐Step Synthesis of Galanthamine from Commercially Available Materials. Issue 35 (17th November 2016)

• Record Type: Journal Article
• Authors: Nugent, Jeremy; Banwell, Martin G.
• Is Part Of: European journal of organic chemistry. Issue 35(2016)
• Page Start: 5862
• Page End: 5867
• Publication Date: 2016-11-17
• Subjects: Alkaloids -- Heck reaction -- Mitsunobu reaction -- Amination -- Synthesis design; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201601085
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : Narwedine, an immediate precursor to the therapeutically valuable alkaloid (–)‐galanthamine, has been synthesised by engaging an iodinated isovanillin derivative in an intermolecular Mitsunobu reaction with a 2‐cyclohexen‐1‐ol derivative. The resulting aryl ether participated in an exceptionally efficient intramolecular Heck reaction to give a tetracyclic lactol after the hydrolysis of the primary cyclisation product. This last compound is an advanced intermediate associated with the Magnus synthesis of narwedine and could be elaborated to narwedine itself under reductive amination conditions. As a result, an eleven‐step synthesis of galanthamine has been established. Abstract : The alkaloid galanthamine, which is used for the clinical treatment of Alzheimer's disease, is prepared over eleven steps (longest linear sequence) from commercially available materials. The two key steps are an intermolecular Mitsunobu reaction and a Heck cyclisation that ultimately provide racemic narwedine, an established precursor to either enantiomeric form of galanthamine.