Enamines and diastereo-selective reduction of enamines

1. An isolated compound of Formula A:

wherein:

m is 1 or 2;

p is 0, 1, or 2;

q is 0;

W is C;

Z is CH 2 ;

Y is NH, O, S, or CH2;

X 1 and X 2 are hydrocarbons which together contain a total of five to nine carbon atoms and which link together such that the moiety:

 forms a bridged bicyclic ring system;

R 1 , R 2 and R 3 are independently H or C 1-3 alkyl;

R 4 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, or C 3-6 cycloalkenyl, each of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with at least one group selected from OH, halo, CN, C 1-3 alkoxy, and NH 2 .

2. An isolated compound which is selected from the following compounds:

3. An isolated compound which is selected from the following compounds

4. An isolated compound which is selected from the following compounds

5. A method of synthesizing a compound of Formula B or a salt thereof, comprising:

contacting an isolated compound of Formula A with a reducing agent in an aprotic polar or non-polar solvent optionally comprising an acid

and, optionally, purifying the compound of Formula B, wherein the compound of Formula B is:

 or a salt thereof, and wherein the compound of Formula A is:

6. The method of claim 5 , wherein the reducing agent is selected from boron hydrides and silicon hydrides.

7. The method of claim 6 , wherein the silicon hydride is selected from Et 3 SiH, HSiCl 3 , HSiPh 3 , and HSiPh(CH 3 ) 2 .

8. The method of claim 7 , wherein the silicon hydride is Et 3 SiH.

9. The method of claim 7 , wherein the silicon hydride is HSiCl 3 .

10. The method of claim 7 , wherein the silicon hydride is HSiPh 3 .

11. The method of claim 7 , wherein the silicon hydride is HSiPh(CH 3 ) 2 .

12. The method of claim 6 , wherein the boron hydride is selected from NaBH 4 , NaBH(OAc) 3 , NBu 4 BH 4 , NaBH(OAc) 3 , NaCNBH 3 , and NMe 4 BH(OAc) 3 .

13. The method of claim 12 , wherein the boron hydride is NaBH 4 .

14. The method of claim 12 , wherein the boron hydride is NaBH(OAc) 3 .

15. The method of claim 12 , wherein the boron hydride is NBu 4 BH 4 .

16. The method of claim 12 , wherein the boron hydride is NaBH(OAc) 3 .

17. The method of claim 12 , wherein the boron hydride is NaCNBH 3 .

18. The method of claim 12 , wherein the boron hydride is NMe 4 BH(OAc) 3 .

19. The method of claim 5 , wherein the aprotic polar or non-polar solvent is selected from xylenes, toluene, alkanes, CHCl 3 , CH 2 Cl 2 , methyl tert-butyl ether, acetonitrile, propionitrile, tetrahydrofuran, and 2-methyl tetrahydrofuran.

20. The method of claim 5 , wherein the optional acid is a C 1 to C 10 carboxylic acid.

21. The method of claim 20 , wherein the C 1 to C 10 carboxylic acid is acetic acid or hexanoic acid.

22. The method of claim 5 , wherein the compound of Formula B obtained before the optional purification has an exo:endo isomer ratio greater than or equal to 70:30, greater than or equal to 75:25, greater than or equal to 80:20, greater than or equal to 85:15, greater than or equal to 90:10, greater than or equal to 95:5, or greater than or equal to 99:1.

23. The method of claim 5 , wherein the compound of Formula B obtained before the optional purification has an endo:exo isomer ratio greater than or equal to 70:30, greater than or equal to 75:25, greater than or equal to 80:20, greater than or equal to 85:15, greater than or equal to 90:10, greater than or equal to 95:5, or greater than or equal to 99:1.

24. The method of claim 5 , wherein the compound of Formula B is further converted to a pharmaceutically acceptable salt.

25. An isolated compound which is:

26. The method of claim 5 , wherein the method also comprises contacting at reflux a mixture of a ketone of Formula C, a secondary amine of Formula D or a salt thereof, and an acidic catalyst in a non-polar solvent to obtain the compound of Formula A:

27. The method of claim 26 , wherein the non-polar solvent is xylenes.

28. The method of claim 26 , wherein the catalytic acid hexanoic acid.

29. The method of claim 26 , wherein the water produced by the reaction between the ketone of Formula C and the amine of Formula D is removed using a sieve dryer or Dean-Stark apparatus.

30. The method of claim 26 , wherein the compound of Formula A is isolated by crystallization.

31. The method of claim 30 , wherein the crystallization is accomplished by cooling the reaction mixture to room temperature, adding another non-polar solvent, optionally seeding the mixture with the previously formed compound of Formula A, and collecting the solid compound of Formula A.

32. The method of claim 26 , wherein the non-polar solvent is hexane, heptane, or octane.