Methods of making lubiprostone and intermediates thereof

1. A process for preparation of Lubiprostone comprising hydrogenation, in the presence of a suitable hydrogenation catalyst, of a compound of Formula 10:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 6 is H or C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

S/D is a single or a double bond;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

2. The process of claim 1 wherein the hydrogenation is performed using hydrogen gas.

3. The process of claim 1 wherein the suitable hydrogenation catalyst is selected from the group consisting of palladium, platinum, rhodium, ruthenium, and Raney-nickel.

4. The process of claim 1 wherein the suitable hydrogenation catalyst is palladium on carbon.

5. The process of claim 4 wherein the suitable hydrogenation catalyst is 10 wt % palladium on carbon (dry basis), 50 wt % (wet support).

6. The process of claim 1 wherein the S/D is a double bond.

7. The process of claim 1 wherein the compound of Formula 10 is a compound of Formula 18:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 6 is H or C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

8. The process of claim 7 wherein the compound of Formula 18 is a compound of Formula 18a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

9. The process of claim 8 wherein the compound of Formula 18a is prepared by reacting, in the presence of a seventh base selected from the group consisting of: alkali hydroxides, Zn(OH) 2 , mixtures of ammonia and alkali hydroxides, and mixtures thereof, a compound of Formula 17a:

with a compound of Formula 12:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 4 and R 5 are independently a short chain alkyl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

10. The process of claim 9 wherein the compound of Formula 17a is prepared by oxidizing a compound of Formula 16a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of 1-1, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

11. The process of claim 10 wherein the compound of Formula 16a is prepared by deprotection of a compound of Formula 15:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl; and

R 8 is a silyl protecting group;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

12. The process of claim 8 wherein the compound of Formula 18a is prepared by oxidizing a compound of Formula 23:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

13. The process of claim 12 wherein oxidizing comprises using an oxidizing agent selected from the group consisting of: Dess-Martin periodinane, CrO 3 , MnO 2 , 2,2,6,6-tetramethyl-piperidinyloxy free radical/sodium hypochlorite, SO 3 /pyridine and oxalyl chloride/dimethylsulfoxide/triethylamine.

14. The process of claim 13 wherein the oxidizing agent is Dess-Martin periodinane.

15. The process of claim 12 wherein oxidizing comprises using a eighth solvent selected from the group consisting of: dichloromethane, dimethylsulfoxide, and mixtures thereof.

16. The process of claim 11 wherein the compound of Formula 15 is prepared by reacting, in the presence of a ninth base selected from the group consisting of triethylamine, diisopropylamine, diisopropylethylamine, pyridine and 1,8-Diazabicyclo[5.4.0]undec-7-ene, a compound of having a structure of R 7 -G, wherein G is a leaving group and R 7 is C(R 1′ )(R 2′ )(R 3′ ), with a compound of Formula 14:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 6 is H; and

R 8 is a silyl protecting group;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

17. The process of claim 16 wherein G is selected from the group consisting of: chlorine, bromine, iodine, methansulfonyloxy, trifluoromethansulfonyloxy and p-toluenesulfonyloxy.

18. The process of claim 16 wherein R 7 -G is a benzyl halide.

19. The process of claim 16 wherein the ninth base is selected from the group consisting of: triethylamine, diisopropylamine, pyridine and 1,8-Diazabicyclo[5.4.0]undec-7-ene.

20. The process of claim 1 wherein the compound of Formula 10 is prepared by oxidation of a compound of Formula 9:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 6 is H or C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

X is OH or O; and

each S/D is independently a single or a double bond;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

21. The process of claim 20 wherein oxidation is performed using an oxidizing agent selected from the group consisting of Dess-Martin periodinane, o-iodoxybenzoic acid, CrO 3 , MnO 2 , 2,2,6,6-tetramethyl-piperidinyloxy free radical/sodium hypochlorite and SO 3 /pyridine.

22. The process of claim 20 wherein oxidation is conducted in a fourth solvent, the fourth solvent comprising dichloromethane.

23. The process of any one of claims 1 or 20 wherein the compound of Formula 10 that is hydrogenated to Lubiprostone is a compound of Formula 10a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl; and

S/D is a single or a double bond;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

24. The process of any one of claims 1 , 7 , 8 , 9 , 10 , 11 , 12 , and 20 wherein hydrogenation comprises using ethyl acetate.

25. The process of any one of claims 1 and 20 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a single bond.

26. The process of any one of claims 1 and 20 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a double bond.

27. The process of any one of claims 1 and 20 wherein the reaction comprises a mixture of compounds of Formula 10 wherein the mixture comprises compounds in which the S/D bond between carbon 9b1 and carbon 9b2 is a single bond and compounds in which the S/D bond between carbon 9b1 and carbon 9b2 is a double bond.

28. A compound of Formula 15:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ ), where R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl; and

R 8 is a silyl protecting group;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

29. A compound of Formula 16a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ ), where R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

30. A compound of Formula 17a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ ), where R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

31. A compound of Formula 18a:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 7 is C(R 1′ )(R 2′ )(R 3′ ), where R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; and

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

32. A compound selected from the group consisting of: (3aR,4S,5R,6aS)-5-(phenylmethoxy)-4-(triisopropylsilyloxymethyl)hexahydrocyclopenta[b]furan-2-ol; (5Z)-7-[(1R,2S,3R,5S)-3-Benzyloxy-5-hydroxy-2-[(triisopropylsilyloxy)methyl]cyclopentyl]hept-5-enoic acid; Benzyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-3-(2-phenylmethoxy)-2-(triisopropylsilyloxymethyl)cyclopentyl]-5-heptanoate; (5Z)-Benzyl 7-[(1R,2S,3R,5S)-3-benzyloxy-5-hydroxy-2-(hydroxymethyl)cyclopentyl]hept-5-enoate; (5Z)-Benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl 5-oxocyclopentyl]hept-5-enoate; Benzyl (Z)-7-[(1R,2S,3R,5S)-2-(triisopropylsilyloxymethyl)-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate; Benzyl (Z)-7-[(1R,2S,3R,5S)-2-hydroxymethyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate; Benzyl (Z)-7-[(1R,2S,3R,5S)-2-formyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate; Benzyl (Z)-7-[(1R,2R,3R,5S)-5-(2-tetrahydropyranyloxy)-2-((E)-3-oxo-1-octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate; and Benzyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-((E)-3-oxo-1-octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate.

33. A compound of Formula 10:

wherein R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1 , R 2 and R 3 is aryl or substituted aryl;

R 6 is H or C(R 1′ )(R 2′ )(R 3′ );

R 1′ , R 2′ and R 3′ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

at least one of R 1′ , R 2′ and R 3′ is aryl or substituted aryl; and

S/D is a single or a double bond;

wherein

alkyl refers to a straight chain, branched chain or cyclic alkyl group of 1 to 10 carbon atoms, that may be fully saturated, mono- or polyunsaturated;

aryl refers to a polyunsaturated, aromatic hydrocarbon of from 1 to 3 rings that are either fused or covalently linked, optionally containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized;

arylalkyl refers to groups in which an aryl group is attached to an alkyl group, optionally where a methylene carbon of the alkyl group is replaced by an oxygen atom; and

the substitution of the alkyl, aryl or arylalkyl group refers to the presence of one or more substituents selected from the group consisting of alkyl or alkoxy of from 1 to 10 carbons, halogen, NO 2 and trifluoromethyl.

34. A compound selected from the group consisting of: (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde; (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan; (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-1-octyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan; (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol; (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol; (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxy-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol; (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol; (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid; (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid; (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid; (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid; Benzyl (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate; Benzyl (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate; Benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate; Benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate; (Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid; (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid; Benzyl (Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate; and Benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate.