Total synthesis of galanthamine, analogues and derivatives thereof

Abstract

The invention relates to a method for the synthesis of galanthamine, the derivatives and analogues thereof of formula (1) where R 1 =a hydrogen atom, R 2 =a hydroxy group, R 1 and R 2 together form ═O, R 3 , R 4 , and R 5 independently=a hydrogen atom, a hydroxy group or a (C 1 -C 2 )alkoxy group, R 6 ═H, (C 1 -C 12 )alkyl, (CH 2 ) n NR 7 R 8 , or —(CH 2 ) n N + R 7 R 8 R 9 where n=1 to 12, Z=two hydrogen atoms, or an oxygen atom and X=an oxygen, sulphur or nitrogen atom, or a —SO, —SO 2 , or —NR 6 group where R 6 is as defined above or is an amine protecting group.

1. A method of synthesizing compounds of formula (1) 
                 
 
       in which
 either R 1  represents a hydrogen atom and R 2  represents a hydroxyl group, or R 1  and R 2  together form═O,  
 R 3 , R 4  and R 5  represent each independently of one another a hydrogen atom, a hydroxyl group or a (C 1 -C 12 )alkoxy group,  
 R 6  represents a hydrogen atom, a (C 1 -C 12 )alkyl group, a group —(CH 2 ) n NR 7 R 8  or a group —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, R 7  and R 8  represent each independently of one another a hydrogen atom; a cyano; (C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkenyl; (C 1 -C 4 )alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; and R 9  represents a hydrogen atom or a cyano, (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl, aryl (C 1 -C 4 )alkenyl, alkylcarbonyl or arylcarbonyl radical, the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals;  
 Z represents either two hydrogen atoms or one oxygen atom, and  
 X represents alternatively an oxygen atom or a sulfur atom on an —SO group or an —SO 2  group or a group —NR 6  where R 6  is as defined above or represents an amine-protective group,  
 comprising providing an α,β-ethylenic ketone of formula (10) 
                 
 
 
       and oxidizing said ketone to a spirodienone of formula (11) 
                 
 
       wherein said spirodienone of formula (11) is thereafter transformed to produce a compound of formula (1). 
     
     
       2. A method according to  claim 1 , characterized in that the oxidation is performed in the presence of benzeneselininic anhydride and a support. 
     
     
       3. A method according to  claim 2 , characterized in that the support is selected from the group consisting of molecular sieves and mixtures of silica and alumina. 
     
     
       4. A method according to  claim 3 , characterized in that the mixture of silica and alumina is a 50/50 mixture. 
     
     
       5. A method according to  claim 1 , characterized in that a compound of formula (6) 
                 
 
       in which Hal represents a halogen atom selected from bromine and iodine atoms, R 3 , R 4 , and R 5  are as defined in  claim 1 , and R 10  represents an amine group or a hydroxyl group is reacted with (1,4-dioxaspiro[4.5]dec-7-en-8-yl)acetic acid of formula (7), 
                 
 
       and a compound of formula (8) 
                 
 
       is obtained which is cyclized by an intramolecular Heck reaction to give a compound of formula (9) 
                 
 
       in the presence of a palladium or a palladium(0) precursor catalyst and of bidentate alkylphosphine ligands in a solvent, then the dixolane function of the compound of formula (9) is deprotected to give the α,β-ethylenic ketone of formula (10) 
                 
 
       which is oxidized in the presence of benzeneseleninic anhydride, to which a mixture of silica and alumina has been added, to give a compound of formula (11) 
                 
 
       which is reacted with an amine of formula NHR 6  where R 6  is as defined in  claim 1  to give, by opening of the lactone, the corresponding amide of formula (12) 
                 
 
       which is cyclized to give a compound of formula (1a), 
                 
 
       which is optionally subjected to a diastereoselective reduction to give the corresponding derivative of formula (1b), 
                 
 
       whose amide function can optionally be reduced to give a compound of formula (1c) 
                 
 
     
     
       6. A method according to  claim 5 , characterized in that the compound of formula (12) is resolved and then the synthesis is continued to give the compounds of formula (1a) to (1c) in their optically active forms. 
     
     
       7. A method according to  claim 5 , characterized in that the compound of formula (1a) is resolved and then the synthesis is continued to give the compounds of formula (1b) to (1c) in their optically active forms. 
     
     
       8. A method according to  claim 1 , characterized in that galanthamine is prepared in the form of the racemate or of its optically pure isomers. 
     
     
       9. Compound of formula (11) 
                 
 
       in which R 3 , R 4  and R 5  represent each independently of one another a hydrogen atom, a hydroxyl group or a (C 1 -C 12 )alkoxy group and X represents alternatively an oxygen atom or a sulfur atom or an —SO group or an —SO 2  group or a group —NR 6  where R 6  represents a hydrogen atom, a (C 1 -C 12 )alkyl group, a group —(CH 2 ) n NR 7 R 8  or a group —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, R 7  and R 8  represent each independently of one another a hydrogen atom; a cyano; (C 1 -C 4 )alkyl; aryl(C 1 C 4 )alkyl; aryl(C 1 -C 4 )alkenyl; (C 1 -C 4 )alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group. 
     
     
       10. Compounds according to  claim 9 , characterized in that R 3 =OCH 3 , R 4 =R 5 =H and X=O, NH or N—CH 3 . 
     
     
       11. Compound of formula (8) 
                 
 
       in which Hal represents a halogen atom selected from bromine and iodine atoms, and R 3 , R 4 , and R 5  represent each independently of one another a hydrogen atom, a hydroxyl group or a (C 1 -C 12 )alkoxy group; and X represents alternatively an oxygen atom or a sulfur atom or a nitrogen atom or an —SO group, an —SO 2  group or a group —NR 6  where R 6  represents a hydrogen atom, a (C 1 -C 12 )alkyl group, a group —(CH 2 ) n NR 7 R 8  or a group —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, R 7  and R 8  represent each independently of one another a hydrogen atom; a cyano; (C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkenyl; (C 1 -C 4 )alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group. 
     
     
       12. Compounds according to  claim 11 , characterized in that Hal=I, R 3 =OCH 3 , R 4 =R 5 =H and X=NH or N—CH 3 . 
     
     
       13. Compound of formula (12) 
                 
 
       in which R 3 , R 4  and R 5  represent each independently of one another a hydrogen atom, a hydroxyl group or a (C 1 -C 12 )alkoxy group; and R 6  represents a hydrogen atom, a (C 1 -C 12 )alkyl group, a group —(CH 2 ) n NR 7 R 8  or a group —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, R 7  and R 8  represent each independently of one another a hydrogen atom; a cyano; (C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkenyl; (C 1 -C 4 )alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; and X represents alternatively an oxygen atom or a sulfur atom or an —SO group or an —SO 2  group or a group —NR 6  where R 6  is as defined above or represents an amine-protective group. 
     
     
       14. Compound of formula (9) 
                 
 
       in which Hal, R 3 , R 4 , and R 5  are as defined in  claim 1  and X represents alternatively an oxygen atom or sulfur atom or a nitrogen atom or an —SO group, an —SO 2  group or a group —NR 6  where R 6  represents a hydrogen atom, a (C 1 -C 12 )alkyl group, a group —(CH 2 ) n NR 7 R 8  or a group —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, R 7  and R 8  represent each independently of one another a hydrogen atom; a cyano; (C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkyl; aryl(C 1 -C 4 )alkenyl; (C 1 -C 4 )alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group. 
     
     
       15. The process of  claim 2  wherein said support is an inorganic support. 
     
     
       16. A compound according to  claim 11  as follows:
                     17 . A compound according to  claim 14  as follows: