Outline
In 1962 racemic galanthamine and epi-galanthamine were prepared by organic reduction of racemic narwedine by D. H. R. Barton. Narwedine is the related enone (galanthamine the allyl alcohol) obtained in an oxidative coupling. Chemical yield: 1.4%. In addition they isolated (-)-narwardine by chiral resolution from a mixture of racemix narwedine and 0.5 equivalents of (+)-galanthamine. In this way they were able to obtain (-)galanthamine again by reduction In 1976 Kametani obtained both galanthamine enantiomers by using a derivative of tartaric acid as a chiral resolving agent. In 1977 Koga obtained both enantiomers via a chiral pool synthesis starting from L-tyrosine and in 1988 Carrol optimized the oxidative coupling route to 11% yield based on isovanillin
In 1989 Vlahov exploited asymmetric reduction by biocatalysis in the synthesis of several galanthamine precursors. and in 1994 Shieh & Carlson obtained (-)-galanthamine by spontaneous resolution of its narwedine precursor. Racemic narwedine was treated with 0.01 equivalent of (+)-galanthamine resulting in a 76% yield. Narwedine is a racemic conglomerate allowing the isolation of the S,S enantiomer from the R,R enantiomer by simple crystallization. What made the process unique is that both enantiomers are in dynamic chemical equilibrium with each other though a common phenol in a Michael reaction-like reaction brought about by triethylamine.
| Resolution of Narwedine |
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In 1999 Jordis performed (-)-galanthamine synthesis on a multikilogram scale based on Carrol chemistry and Shieh/Carlson chiral resolution. This would become the basis for current industrial production by Sanochemia (AT). 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. Improved methods were published in 2002 and 2005 (see below) In 2004 Node obtained (-)-galanthamine via a remote asymmetric induction method with starting chiral compound D-phenylalanine. Brown prepared (-)-galanthamine in 2007 starting from isovanillin. Isovanillin was also used by Magnus (2009) D-glucose was used by Chida (2010).
Syntheses of racemic galanthamine have been reported by Wang in 2006 and by Saito in 2008.
Read more about this topic: Galanthamine Total Synthesis
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