Kinetic resolution

1. A method of resolving a mixture of stereoisomers of a thiol comprising the step of preferentially acylating one thiol stereoisomer in the presence of a bifunctional organocatalyst; wherein the bifunctional organocatalyst is selected from the group consisting of:

wherein Z is a C 1 to C 5 carbon chain optionally comprising at least one C—C unsaturated bond, and optionally substituted one or more times with at least one of a halogen, cyano, CF 3 , NO 2 , C 1 -C 5 ketone, C 1 -C 5 ester, C 1 -C 10 amide, C 1 -C 5 sulfone, C 1 -C 5 sulfoxide and combinations thereof; and

M is H, OH, or OMe.

2. A method according to claim 1 wherein the mixture of stereoisomers of the thiol is an enantiomeric mixture of the thiol.

3. A method according to claim 1 wherein the thiols are selected from the group consisting of primary thiols and secondary thiols.

4. A method according to claim 1 wherein the bifunctional organocatalyst comprises a cinchona alkaloid.

5. A method according to claim 4 wherein the cinchona alkaloid is substituted with a urea, thiourea or sulfonamide functional group.

6. A method according to claim 1 wherein the step of acylating the thiol comprises reacting the thiol with an organic anhydride.

7. A method according to claim 6 wherein the organic anhydride is selected from the group consisting of:

wherein R 1 and R 2 are the same or different and are selected from the group consisting of C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl and combinations thereof, optionally substituted with at least one of a halogen, cyano, or C 1 -C 5 fluoroalkyl;

R 3 and R 4 are the same or different and are selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl and combinations thereof, optionally substituted with at least one of a halogen, cyano, or C 1 -C 5 fluoroalkyl, such that at least one of R 3 and R 4 is H;

R 5 and R 6 are the same or different and are selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl and combinations thereof, optionally substituted with at least one of a halogen, cyano, or C 1 -C 5 fluoroalkyl; and

n is 0-5.

8. A process for the preparation of enantioenriched 3-(aminomethyl)-5-methylhexanoic acid comprising the steps of:

i) preferentially acylating one thiol enantiomer of an enantiomeric mixture of the thiol with 3-isobutylglutaric anhydride in the presence of a bifunctional organocatalyst;

wherein the bifunctional organocatalyst is selected from the group consisting of:

wherein Z is a C 1 to C 5 carbon chain optionally comprising at least one C—C unsaturated bond, and optionally substituted one or more times with at least one of a halogen, cyano, CF 3 , NO 2 , C 1 -C 5 ketone, C 1 -C 5 ester, C 1 -C 10 amide, C 1 -C 5 sulfone, C 1 -C 5 sulfoxide and combinations thereof; and

M is H, OH, or OMe;

and

ii) converting the thioester functional group into an amine.

9. A process according to claim 8 wherein the step of converting the thioester functional group into an amine comprises:

i) aminolysis of the thioester functional group to yield an amide; and

ii) subjecting the amide product of step iii) to a Hofmann rearrangement.

10. A molecule having the general structure:

wherein Z is a C 1 to C 5 carbon chain optionally comprising at least one C—C unsaturated bond, and optionally substituted one or more times with at least one of a halogen, cyano, CF 3 , NO 2 , C 1 -C 5 ketone, C 1 -C 5 ester, C 1 -C 10 amide, C 1 -C 5 sulfone, C 1 -C 5 sulfoxide and combinations thereof; and

M is H, OH, or OMe.

11. A molecule of claim 10 wherein the molecule is an acylation catalyst in the resolution of a mixture of stereoisomers of a thiol.

12. A method according to claim 1 , wherein the step of acylating the thiol comprises reacting the thiol with an organic anhydride, wherein the organic anhydride is a prochiral anhydride and wherein acylation of the thiol with the prochiral anhydride in the presence of the bifunctional organocatalyst proceeds with desymmetrisation of the prochiral anhydride to afford a thioester.

13. A method according to claim 12 wherein the prochiral anhydride is of the general formula:

wherein R 3 and R 4 are the same or different and are selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl and combinations thereof, optionally substituted with at least one of a halogen, cyano, or C 1 -C 5 fluoroalkyl, such that at least one of R 3 and R 4 is H; and n is 1.

14. A method according to claim 1 , wherein the step of acylating the thiol comprises reacting the thiol with an organic anhydride, wherein the organic anhydride is a meso anhydride and wherein acylation of the thiol with the meso anhydride in the presence of the bifunctional organocatalyst proceeds with desymmetrisation of the meso anhydride to afford a thioester; wherein the thioester is at least one of enantiomerically or diastereomerically enriched.

15. A method according to claim 14 , wherein the meso anhydride is of the general formula:

wherein R 5 and R 6 are the same and are selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl and combinations thereof, optionally substituted with at least one of a halogen, cyano, or C 1 -C 5 fluoroalkyl.

16. A method according to claim 12 wherein the thioester is at least one of enantiomerically or diastereomerically enriched.

17. A method according to claim 13 wherein the thioester is at least one of enantiomerically or diastereomerically enriched.

18. A method according to claim 12 wherein the thiols are selected from the group consisting of primary thiols and secondary thiols.

19. A method according to claim 13 wherein the thiols are selected from the group consisting of primary thiols and secondary thiols.