Galanthamine Total Synthesis - Eli Lilly / U. of Southampton Galanthamine Synthesis

Eli Lilly / U. of Southampton Galanthamine Synthesis

A total synthesis reported by Eli Lilly and the University of Southampton in 2007 also starts from isovanillin. The aldehyde group in its derivative 1 is converted to its amine by reductive amination with methylamine which is then protected as a BOC group in 2. The remainder of the carbon framework is added with chiral propargyl alcohol 3 (introducing the 4a stereocenter and obtained by chiral synthesis of the ketone with R-Alpine borane) in a Mitsunobu reaction to aryl ether 4. The trimethylsilyl protective group is removed by potassium carbonate in methanol and the subsequent enyne metathesis reaction with Grubbs' catalyst gives diene 5. A Hydroboration-oxidation reaction converts 5 to alcohol 6 and an intramolecular heck reaction affords tricycle 7 with alkene isomerization and establishment of the 8a stereocenter with correct stereochemistry based on chiral induction. The allyl alcohol group in 8 is introduced by selenoxide oxidation with an excess of the desired diastereomer. In the final step to galanthamine 9 the hydroxyl group is activated as the triflate and the amine group as the mesylate for intramolecular azepine ring closure via nucleophilic substitution (with 6% epimer formation).