The natural source of galantamine are certain species of daffodil and because these species are scarce and because the isolation of galanthamine from daffodil is expensive (a 1996 figure specifies 50,000 US dollar per kilogram, the yield from daffodil is 0.1–0.2% dry weight) alternative synthetic sources are under development by means of total synthesis.
Outline
Galanthamine numbering scheme and stereocenters
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 racemic 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[2][3] 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 [4] 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 through a common phenol in a Michael reaction-like reaction brought about by triethylamine.
Resolution of Narwedine
Resolution of Narwedine
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 intramolecularHeck 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.[5] Brown prepared (−)-galanthamine in 2007 starting from isovanillin.[6] Isovanillin was also used by Magnus (2009) [7] D-glucose was used by Chida (2010).[8]
Syntheses of racemic galanthamine have been reported by Wang in 2006 [9] and by Saito in 2008.[10]
Sanochemia industrial production
The method outlined by Jordis in 1999 forms the basis for industrial galanthamine production.[11]
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.
reduction of (−)-narwedine to (−)-galanthamine as the bromide
reduction of (−)-narwedine to (−)-galanthamine as the bromide
This final step is enantioselective producing the desired S,S,R compound because the approach of H− is restricted to the Si face as the Re face is shielded by the DB ring system. Formation of the S,S,S epimer is also avoided by keeping the reaction temperature below −15°C.
↑ Synthesis and Pharmacology of Galantamine José Marco-Contelles, Maria do Carmo Carreiras, Carolina Rodríguez, Mercedes Villarroya, and Antonio G. García Chem. Rev.; 2006; 106(1) pp 116–133; (Review) doi:10.1021/cr040415t
↑ Koga, Kenji; Tomioka, Kiyoshi; Shimizu, Kimihiro; Yamada, Shun-Ichi (1977). "Approaches to the Biogenetic-type Asymmetric Synthesis of Some Amaryllidaceae Alkaloids". Heterocycles. 6 (9): 1752. doi:10.3987/R-1977-09-1752 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
↑ Koga, Kenji; Shimizu, Kimihiro; Tomioka, Kiyoshi; Yamada, Shun-Ichi (1977). "A Biogenetic-type Asymmetric Synthesis of Optically Active Amaryllidaceae Alkaloids: (+)- and (−)-Galanthamine from L-Tyrosine". Heterocycles. 8: 277. doi:10.3987/S(S)-1977-01-0277 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
↑ Asymmetric Transformation of Either Enantiomer of Narwedine via Total Spontaneous Resolution Process, a Concise Solution to the Synthesis of (−)-Galanthamine Wen-Chung Shieh and John A. Carlson J. Org. Chem.; 1994; 59(18) pp 5463–5465; doi:10.1021/jo00097a060
↑ Kodama, Sumiaki; Hamashima, Yoshio; Nishide, Kiyoharu; Node, Manabu (2004). "Total Synthesis of (−)-Galanthamine by Remote Asymmetric Induction". Angewandte Chemie International Edition. 43 (20): 2659–2661. doi:10.1002/anie.200353636. PMID18629982.
1 2 Satcharoen, Vachiraporn; McLean, Neville J.; Kemp, Stephen C.; Camp, Nicholas P.; Brown, Richard C. D. (2007). "Stereocontrolled Synthesis of (−)-Galanthamine". Organic Letters. 9 (10): 1867–1869. doi:10.1021/ol070255i. PMID17429978.
↑ Magnus, Philip; Sane, Neeraj; Fauber, Benjamin P.; Lynch, Vince (2009). "Concise Syntheses of (−)-Galanthamine and (±)-Codeine via Intramolecular Alkylation of a Phenol Derivative". Journal of the American Chemical Society. 131 (44): 16045–16047. doi:10.1021/ja9085534. PMID19835379.
↑ Ishikawa, Teruhiko; Kudo, Kazuhiro; Kuroyabu, Ken; Uchida, Satoshi; Kudoh, Takayuki; Saito, Seiki (2008). "Domino Double Michael−Claisen Cyclizations: A Powerful General Tool for Introducing Quaternary Stereocenters at C(4) of Cyclohexane-1,3-diones and Total Synthesis of Diverse Families of Sterically Congested Alkaloids". The Journal of Organic Chemistry. 73 (19): 7498–7508. doi:10.1021/jo801316s. PMID18781800.
↑ Development of a Pilot Scale Process for the Anti-Alzheimer Drug (−)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion Bernhard Küenburg, Laszlo Czollner, Johannes Fröhlich, and Ulrich Jordis Org. Process Res. Dev.; 1999; 3(6) pp 425–431; (Article) doi:10.1021/op990019q
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