Diastereoselective preparation of bicyclo[2.2.2]octan-2-one compounds

1. A process for the synthesis of (1R*,4R*,5S*,6S*)-6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one compounds, the compounds of the formula (II):

said process comprising a cyclization of:

2-cyclohexen-1-one, and

a compound of the formula Ar—CH 2 —CHO, wherein Ar represents an aryl group;

wherein said process is conducted:

in absence of a chiral base;

in the presence of

proline; and

a solvent selected from the group consisting of an aromatic solvent, an ether solvent, a chlorinated organic solvent, and an ester; or a mixture thereof; wherein said solvent is present in an amount of about 1 to 10 vol with respect to 2-cyclohexen-1-one;

and either in the presence of an achiral base or in absence of a base;

wherein said compound of formula (II) is isolated from the reaction mixture by solid-liquid separation.

2. The process according to claim 1 , wherein said process is conducted in the presence of an achiral base.

3. The process according to claim 2 , wherein said achiral base is an achiral N-containing base.

4. The process according to claim 3 , wherein said achiral N-containing base is selected from the group consisting of NR 1 R 2 R 3 , wherein R 1 , R 2 , and R 3 independently represent achiral C 1 -C 8 -alkyl; 1,4-diazabicyclo[2.2.2]octane; 1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diazabicyclo(4.3.0)non-5-ene; and pyridine, wherein the pyridine is unsubstituted, or

mono-, di-, or tri-substituted with methyl.

5. The process according to claim 1 , wherein said process is performed in the presence of enantiomerically enriched D- or L-proline.

6. The process according to claim 5 , wherein said process is performed in the presence of an aromatic solvent, or an ether solvent.

7. The process according to claim 2 , wherein said achiral N-containing base is present in an amount of about 0.1 equ. to 0.5 equ. with respect to 2-cyclohexen-1-one.

8. The process according to claim 7 , wherein proline is present in an amount of about 0.05 equ. to 0.5 equ. with respect to 2-cyclohexen-1-one.

9. The process according to claim 8 , wherein said compound of the formula Ar—CH 2 —CHO is present in an amount of about 1 equ. to 2 equ. with respect to 2-cyclohexen-1-one.

10. The process according to claim 9 , wherein said solvent is present in an amount of about 5 to 7 vol with respect to 2-cyclohexen-1-one.

11. The process according to claim 10 , wherein the pH of the reaction mixture is about 8 to 10.

12. The process according to claim 11 , wherein said isolation from the reaction mixture by solid-liquid separation is achieved

by filtration of the precipitated product at the reaction temperature; or

by

1. cooling of the reaction mixture to a temperature below the reaction temperature and

2. filtration of the precipitated product.

13. The process according to claim 1 , wherein the compound of the formula (II) is further transformed to a compound the formula (I):

wherein said transformation of the compound of the formula (II) to the compound of the formula (I) is effected via an elimination step.

14. The process according to claim 13 , wherein the compound of formula (V):

is an intermediate of said elimination step.

15. The process according to claim 4 , wherein said process is performed in the presence of enantiomerically enriched D- or L-proline.

16. The process according to claim 15 , wherein the compound of the formula (II) is further transformed to a compound the formula (I):

wherein said transformation of the compound of the formula (II) to the compound of the formula (I) is effected via an elimination step.

17. The process according to claim 12 , wherein the compound of the formula (II) is further transformed to a compound the formula (I):

wherein said transformation of the compound of the formula (II) to the compound of the formula (I) is effected via an elimination step.

18. The process according to claim 16 , wherein the compound of formula (V):

is an intermediate of said elimination step.

19. The process according to claim 13 , wherein the compound of the formula (I) wherein in this particular case Ar represents phenyl, is further transformed to any one of the following compounds:

rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester,

isobutyric acid (1S,2S,4S)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester; or

isobutyric acid (1R,2R,4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester.

20. The process according to claim 15 , wherein said achiral N-containing base is present in an amount of about 0.1 equ. to 0.5 equ. with respect to 2-cyclohexen-1-one.