Galantamine total synthesis

The article concerns the total synthesis of galanthamine, a drug used for the treatment of mild to moderate Alzheimer's disease.

In 1977 Koga obtained both enantiomers via a chiral pool synthesis starting from L-tyrosine[2][3] and in 1988 Carrol optimized the oxidative coupling route to 11% yield based on isovanillin.

What made the process unique is that both enantiomers are in dynamic chemical equilibrium with each other through a common phenol in a Michael reaction-like reaction brought about by triethylamine.

In 1999 Jordis performed (−)-galanthamine synthesis on a multikilogram scale based on Carrol chemistry and Shieh/Carlson chiral resolution.

In 2000 Fels proposed an intramolecular Heck reaction for the construction of the galanthamine backbone and in the same year Trost & Toste obtained (−)-galanthamine in an asymmetric synthesis involving asymmetric allylic alkylation and an intramolecular Heck reaction.

Enantiopure (−)-narwedine is obtained via the dynamic chiral resolution method pioneered by Shieh/Carlson and in the final step the ketone is reduced to the alcohol with L-selectride.

Next an enantioselective Trost AAA reaction takes place between bromophenol 2 and carbonate 6 to the allyl ether 7.

Next the aldehyde group is protected as an acetal in 8 and this step enables the organic reduction of the ester group to the alcohol 9 with DIBAH and subsequent homologation of this alcohol to a nitrile by Mitsunobu-type reaction using acetone cyanohydrine as the source of cyanide, to yield 10 followed by aldehyde deprotection to 11.

The trimethylsilyl protective group is removed by potassium carbonate in methanol and the subsequent enyne metathesis reaction with Grubbs' catalyst gives diene 5.