- Galanthamine total synthesis
; 2006; 106(1) pp 116 - 133; (Review) DOI|10.1021/cr040415t]
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 50,000US dollar perkilogram , the yield from daffodil is 0.1-0.2% dry weight) alternative synthetic sources are under development by means oftotal synthesis . One recent publication details theenantioselective organic synthesis of galanthamine and also that ofmorphine from a single precursor.ynthetic galanthamine timeline
* 1962: Preparation of
racemic galanthamine and epi-galanthamine by organic reduction of racemic narwedine by D. H. R. Barton. Narwedine is the relatedenone (galanthamine theallyl alcohol ) obtained in an oxidative coupling.Chemical yield : 1.4%. In addition they isolated (-)-narwardine bychiral 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
* 1976: Kametani obtains both galanthamine enantiomers by using a derivative oftartaric acid as achiral resolving agent .
* 1977: Koga obtains both enantiomers via achiral pool synthesis starting fromL-tyrosine .
* 1988: Carrol optimizes the oxidative coupling route to 11% yield based onisovanillin
* 1989: Vlahov exploits asymmetric reduction bybiocatalysis in the synthesis of several galanthamine precursors.
* 1994: Shieh/Carlson ["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. CarlsonJ. Org. Chem. ; 1994; 59(18) pp 5463 - 5465; DOI|10.1021/jo00097a060] obtain (-)-galanthamine byspontaneous 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 dynamicchemical equilibrium with each other though a common phenol in a Michael reaction-like reaction brought about bytriethylamine ::
* 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 (AT).
* 2000:Felse proposes an intramolecularHeck reaction for the construction of the galanthamine backbone.
* 2000: Trost/Toste obtain (-)-galanthamine in anasymmetric synthesis involvingasymmetric allylic alkylation and anintramolecular Heck reaction . Improved methods were published in 2002 and 2005 (see below)
* 2004: Node obtains (-)-galanthamine via a remoteasymmetric induction method with starting chiral compoundD-phenylalanine anochemia industrial production
The method outlined by Jordis in 1999 forms the basis for industrial galanthamine production. ["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 ]
This method starts by
Electrophilic halogenation of 3,4-dimethoxybenzaldehyde 1 (accessible fromisovanillin ) withbromine /acetic acid toorganobromide 2 followed byregioselective demethoxylation withsulfuric acid to phenol 3. This compound reacts in areductive amination (sodium borohydride ) withtyramine 4 toamine 5 which is formylated withethyl formate andformic acid indioxane in the next step to compound 6. Anoxidative phenol coupling takes place next withPotassium ferricyanide andpotassium carbonate intoluene to 7. The C8a-C14 bond is formed in the first step followed by aMichael addition of the other phenolic group to the newly formedenone group. The reaction step creates twostereocenter s leading to twodiastereomeric pairs ofenantiomer s. By the nature of the ABD skeleton the desired S,S/R,R pair is the major product formed and the other pair S,R/R,S is removed in workup. Theketone group is protected as theketal 8 with1,2-propylene glycol enabling theorganic reduction bylithiumaluminiumhydride of both the bromine group and the formyl group. In the second phase the ketal group is removed (hydrochloric acid ) forming racemic (S,S/R,R) narwedine 9.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 theSi face as the Re face is shielded by the DB ring system. Formation of the S,S,Sepimer is also avoided by keeping reaction temperature below -15°C.Trost Galanthamine synthesis
The
total synthesis of galanthamine (Trost 2005) ["Divergent Enantioselective Synthesis of (-)-Galanthamine and (-)-Morphine" Barry M. Trost, Weiping Tang, and F. Dean TosteJ. Am. Chem. Soc. ; 2005; 127(42) pp 14785 - 14803; (Article) DOI: 10.1021/ja054449+ [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja054449%2b Abstract] ] is described as follows (see "scheme 1"): the sequence starts bybromination byelectrophilic aromatic substitution ofisovanillin 1 to bromophenol 2, then by synthesis of the second intermediate 5 by reacting dialdehyde 3 in a coupledaldol reaction andHorner-Wadsworth-Emmons reaction with trimethyl phosphonoacetate 4. Thehydroxyl group is activated as aleaving group byacetylation with trichloroethyl carbonate (Troc) to 6. Next anenantioselective Trost AAA reaction takes place between bromophenol 2 and carbonate 6 to the allyl ether 7. Next thealdehyde group is protected as anacetal in 8 and this step enables the toorganic reduction of theester group to thealcohol 9 withDIBAH and subsequent conversion of this alcohol to anitrile bynucleophilic displacement to 10 followed by aldehyde deprotection to 11. Theintramolecular Heck reaction to 12 creates the dihydrofuran ring.Allylic oxidation byselenium dioxide provides allylic alcohol 13 with the correct stereochemistry. The aldehyde reacts withmethylamine to theimine 14 and reduction of the imine and nitrile byDIBAL-H leading to ring-closure to thehemi-aminal 15 (not isolated) followed by acid quenching gives thealcohol 16. In the final step this alcohol group is reduced to give Galanthamine 17 together with 6% of theepi isomer 18. [abromine ,sodium acetate ,acetic acid ,iron , rt bpotassium carbonate , 2days c Troc-Cl,DMAP ,Pyridine ,dichloromethane dpalladium ,Trost ligand ,triethylamine , dichloromethane e 1.5 mol % TsOH, CH(OMe)3,methanol fDIBAL-H ,toluene , -78 °C, 1 hr gtriphenylphosphine ,acetonecyanohydrin ,DIAD ,diethyl ether h 2.20 mol % TsOH,THF , water i 15 mol %Palladium(II) acetate , 15 mol%dppp , 3 eq. Ag2CO3,toluene , 107 °C jselenium dioxide disodium phosphate dioxane , 150 °C 3 hrs kmethylamine ,methanol l 4 eq.DIBAL-H , m aqueous NaH2PO4 n NaCNBH3]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. ["Stereocontrolled Synthesis of (-)-Galanthamine" Vachiraporn Satcharoen, Neville J. McLean, Stephen C. Kemp, Nicholas P. Camp, and Richard C. D. BrownOrg. Lett. ; 2007; 9(10) pp 1867 - 1869; (Letter) DOI|10.1021/ol070255i] Thealdehyde group in its derivative 1 is converted to itsamine byreductive amination withmethylamine which is then protected as a BOC group in 2. The remainder of the carbon framework is added with chiralpropargyl alcohol 3 (introducing the 4a stereocenter and obtained bychiral synthesis of theketone withR-Alpine borane ) in aMitsunobu reaction toaryl ether 4. Thetrimethylsilyl protective group is removed bypotassium carbonate inmethanol and the subsequentenyne metathesis reaction withGrubbs' catalyst givesdiene 5. AHydroboration-oxidation reaction converts 5 toalcohol 6 and anintramolecular heck reaction affords tricycle 7 withalkene isomerization and establishment of the 8astereocenter with correctstereochemistry based onchiral induction . Theallyl alcohol group in 8 is introduced by selenoxide oxidation with an excess of the desireddiastereomer . In the final step to galanthamine 9 the hydroxyl group is activated as thetriflate and the amine group as themesylate for intramolecularazepine ring closure vianucleophilic substitution (with 6%epimer formation).References
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