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New Syntheses Of Galanthamine And Codeine

A novel combination of reactions shortens the pathway to structurally similar Alzheimer’s medicine and narcotic analgesic

by Stuart A. Borman
November 2, 2009 | A version of this story appeared in Volume 87, Issue 44

By using a novel combination of known reactions, Philip Magnus of the University of Texas, Austin, and coworkers have constructed galanthamine and codeine in fewer steps and with higher yields than in previously reported syntheses (J. Am. Chem. Soc., DOI: 10.1021/ja9085534). Magnus believes the strategy, which can produce either drug from the same intermediate, could lead to new commercial syntheses of galanthamine, an Alzheimer’s medicine, and codeine, a narcotic analgesic agent. The researchers used Suzuki coupling to combine two units of the starting material, bromoisovanillin. They then employed an intramolecular phenol para-alkylation reaction to create a cyclohexadienone intermediate (shown) that contains a difficult-to-make quaternary carbon center. This is the first time the reaction has been used to make that type of product, the researchers note. They subsequently elaborated the intermediate into both drugs. The eight-step asymmetric galanthamine synthesis has 63% overall yield, compared with nine steps and 12% yield for the current commercial synthesis. Magnus’ synthesis of racemic codeine is also shorter and has higher overall yield (20%) than previous methods. Magnus and coworkers are currently modifying the procedure to synthesize codeine enantioselectively.


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