Galanthamine total synthesis concerns the total synthesis of galanthamine, a drug used for the treatment of mild to moderate Alzheimer’s disease.[1]
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. One recent publication details the enantioselective organic synthesis of galanthamine and also that of morphine from a single precursor.
1962: Preparation of racemic galanthamine and epi-galanthamine 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
1977: Koga obtains both enantiomers via a chiral pool synthesis starting from L-tyrosine.
1988: Carrol optimizes the oxidative coupling route to 11% yield based on isovanillin
1989: Vlahov exploits asymmetric reduction by biocatalysis in the synthesis of several galanthamine precursors.
1994: Shieh/Carlson [2] obtain (-)-galanthamine by spontaneous resolution of its narwedine precursor. Racemic narwedine is treated with 0.01 equivalent of (+)-galanthamine resulting in a 76% yield. Narwedine is a racemic conclomerate allowing the isolation of the S,S enantiomer from the R,R enantiomer by simple crystallization. What makes 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:
1999: Jordis performs (-)-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 (USA).
2000:Felse proposes an intramolecular Heck reaction for the construction of the galanthamine backbone.
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.
This final step is enantioselective producing the desired S,S,R compound because 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 reaction temperature below -15°C.
Trost Galanthamine synthesis
The total synthesis of galanthamine (Trost 2005) [4] is described as follows (see scheme 1): the sequence starts by bromination by electrophilic aromatic substitution of isovanillin 1 to bromophenol 2, then by synthesis of the second intermediate 5 by reacting dialdehyde3 in a coupled aldol reaction and Horner-Wadsworth-Emmons reaction with trimethyl phosphonoacetate 4. The hydroxyl group is activated as a leaving group by acetylation with trichloroethyl carbonate (Troc) to 6. 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 to organic reduction of the ester group to the alcohol 9 with DIBAH and subsequent conversion of this alcohol to a nitrile by nucleophilic displacement to 10 followed by aldehyde deprotection to 11. The intramolecularHeck reaction to 12 creates the dihydrofuran ring. Allylic oxidation by selenium dioxide provides allylic alcohol 13 with the correct stereochemistry. The aldehyde reacts with methylamine to the imine14 and reduction of the imine and nitrile by DIBAL-H leading to ring-closure to the hemi-aminal15 (not isolated) followed by acid quenching gives the alcohol 16. In the final step this alcohol group is reduced to give Galanthamine 17 together with 6% of the epi isomer 18.[5]
Eli Lilly / U. of Southampton Galanthamine synthesis
^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
^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
^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
^Divergent Enantioselective Synthesis of (-)-Galanthamine and (-)-Morphine Barry M. Trost, Weiping Tang, and F. Dean Toste J. Am. Chem. Soc.; 2005; 127(42) pp 14785 - 14803; (Article) DOI: 10.1021/ja054449+ Abstract
^Stereocontrolled Synthesis of (-)-Galanthamine Vachiraporn Satcharoen, Neville J. McLean, Stephen C. Kemp, Nicholas P. Camp, and Richard C. D. Brown Org. Lett.; 2007; 9(10) pp 1867 - 1869; (Letter) doi:10.1021/ol070255i