Preparation of bicyclo[2.2.2]octan-2-one compounds

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

wherein the compound of formula (II) is formed in a reaction mixture in diastereomerically enriched form; wherein the major diastereoisomer is (1R*,4R*,5S*,6S*)-6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one:

said process comprising a cyclization of a compound of formula 4:

wherein

Ar represents an aryl group; and

—OR 1 and —OR 2 , together with the carbon atom to which they are attached, represent a ketal group;

wherein said cyclization is performed in presence of:

an aqueous mineral acid; and

a solvent; wherein said solvent is present in an amount of about 1-10 vol. with respect to the compound of formula 4; and

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 compound of formula 4, is obtained from a compound of formula 2:

wherein

Ar represents an aryl group;

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group; and

—COOR 3 represents an ester group.

3. The process according to claim 2 , wherein said compound of formula 4 is obtained from said compound of formula 2

via a direct reduction of the ester group —COOR 3 , or,

via a sequence of reaction steps comprising first a reduction of the ester group —COOR 3 of the compound of formula 2 to the corresponding alcohol of formula 3:

and a subsequent oxidation of said alcohol.

4. The process according to claim 2 , wherein said compound of formula 2:

is obtained by a transition metal-catalyzed alpha-arylation of a carbonyl-containing compound of formula 1:

wherein

Ar represents an aryl group;

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group; and

—COOR 3 represents an ester group.

5. The process according to claim 4 , wherein the compound of formula 1 is used in enantiomerically enriched form.

6. 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.

7. The process according to claim 6 , wherein the compound of formula 6:

is an intermediate of said elimination step.

8. A compound of the formula 4:

wherein

Ar represents an aryl group; and

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group.

9. The compound according to claim 8 selected from the group consisting of:

2-Phenyl-2-((R)-1,4-dioxaspiro[4.5]decan-7-yl)-acetaldehyde; and

2-Phenyl-2-(1,4-dioxaspiro[4.5]decan-7-yl)-acetaldehyde.

10. A compound of the formula 3:

wherein

Ar represents an aryl group; and

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group.

11. The compound according to claim 10 selected from the group consisting of:

2-Phenyl-2-((R)-1,4-dioxaspiro[4.5]decan-7-yl)-ethanol;

2-Phenyl-2-(1,4-dioxaspiro[4.5]decan-7-yl)-ethanol;

rac-(R*)-2-Phenyl-2-((R*)-1,4-dioxaspiro[4.5]decan-7-yl)-ethanol; and

rac-(R*)-2-Phenyl-2-((S*)-1,4-dioxaspiro[4.5]decan-7-yl)-ethanol.

12. A compound of the formula 2:

wherein

Ar represents an aryl group;

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group; and

—COOR 3 represents an ester group.

13. The compound according to claim 12 selected from the group consisting of:

Methyl 2-phenyl-2-((R)-1,4-dioxaspiro[4.5]decan-7-yl)-acetate;

Methyl 2-phenyl-2-(1,4-dioxaspiro[4.5]decan-7-yl)-acetate;

rac-(R*)-Methyl 2-phenyl-2-((R*)-1,4-dioxaspiro[4.5]decan-7-yl)-acetate; and

rac-(R*)-Methyl 2-phenyl-2-((S*)-1,4-dioxaspiro[4.5]decan-7-yl)-acetate.

14. A compound of the formula 6:

wherein

Ar represents an aryl group.

15. The compound according to claim 14 selected from the group consisting of:

(1R,2S,3S,4R)-6-oxo-3-phenylbicyclo[2.2.2]octan-2-yl methanesulfonate; and

rac-(1S*,2R*,3R*,4S*)-6-oxo-3-phenylbicyclo[2.2.2]octan-2-yl methanesulfonate.

16. The process according to claim 3 , wherein said compound of formula 2:

is obtained by a transition metal-catalyzed alpha-arylation of a carbonyl-containing compound of formula 1:

wherein

Ar represents an aryl group;

—OR 1 and —OR 2 , together with the carbon atom to which they are attached to, represent a ketal group; and

—COOR 3 represents an ester group.

17. The process according to claim 2 , 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 6 , 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.