Method of preparing (3R,4S)-3-acetamido-4-allyl-n-(tert-butyl)pyrrolidine-3-carboxamide

1. A salt of an amine compound represented by formula I and a carboxylic acid compound represented by formula A or B:

wherein:

X is O, S, or NR e ;

R a is H, lower alkyl, or lower cycloalkyl;

R b is —CH 2 CH═CH 2 , —(CH 2 ) n CH 2 Z 1 , —(CH 2 ) n C(O)H, or —(CH 2 ) n CO 2 Z 2 ;

R c and R d are independently H, lower alkyl, lower cycloalkyl, silyl, acyl, acyloxy; or R c and R d , together with the N that links them, form an optionally substituted 3- to 6-membered heteroaryl or heterocyclic ring;

R e is H or lower alkyl;

n is 1 or 2;

Z 1 is halogen, alkyl sulfonate, aryl sulfonate, or an alkyl sulfonate optionally substituted with one or more halogen;

Z 2 is H, lower alkyl, or lower cycloalkyl;

A 1 is phenyl or 5-6 membered heteroaryl, and is optionally substituted by up to 4 R 4 ;

A 2 is phenyl or 5-6 membered heteroaryl, and is optionally substituted by up to 4 R 5 ;

R 1 is lower alkyl or lower cycloalkyl;

R 2 and R 3 are independently H, lower alkyl, or lower cycloalkyl; or R 2 and R 3 , together with the N that links them, form an optionally substituted 3- to 6-membered saturated heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from S or O; and

R 4 and R 5 are independently halogen, hydroxyl, nitro, lower alkyl, or lower cycloalkyl.

2. The salt of claim 1 , wherein A 1 and A 2 are phenyl.

3. The salt of claim 1 , wherein A 1 is substituted by one R 4 and A 2 is substituted by one R 5 .

4. The salt of claim 1 , wherein the carboxylic acid compound is represented by formula A or B-I:

5. The salt of claim 1 , wherein the amine compound in the salt has an enantiomeric excess of at least 75% ee.

6. The salt of claim 5 , wherein the carboxylic acid compound in the salt is essentially a single enantiomer.

7. The salt of claim 1 , wherein R a is tent-butyl.

8. The salt of claim 1 , wherein R b is —CH 2 CH═CH 2 .

9. The salt of claim 1 , wherein R c is H.

10. The salt of claim 1 , wherein R d is acetyl or trifluoroacetyl.

11. The salt of claim 1 , wherein X is NH.

12. The salt of claim 1 , wherein X is O.

13. The salt of claim 1 , wherein the amine compound is:

14. The salt of claim 1 , wherein the carboxylic acid compound is represented by formula A.

15. The salt of claim 14 , wherein R 1 is methyl.

16. The salt of claim 1 , wherein the carboxylic acid compound is represented by formula B.

17. The salt of claim 4 , wherein the carboxylic acid compound is represented by formula B-I.

18. The salt of claim 16 , wherein R 2 and R 3 are independently methyl, ethyl, or isopropyl; or R 2 and R 3 , together with the N that links them, form a pyrrolidinyl.

19. The salt of claim 17 , wherein R 4 is methyl.

20. The salt of claim 17 , wherein R 5 is methyl.

21. The salt of claim 1 , wherein the carboxylic acid compound is:

22. A method of preparing the salt of claim 1 by fractional crystallization, comprising:

preparing a crystallization solution comprising the amine compound, essentially a single enantiomer of the carboxylic acid compound, and a solvent; and

crystallizing from the crystallization solution the salt of the amine compound and the carboxylic acid compound.

23. The method of claim 22 , wherein the solvent comprises water, methanol, ethanol, isopropanol, ethyl acetate, or acetonitrile or a mixture of any of these.

24. The method of claim 22 , wherein the amine compound in the salt crystallized from the crystallization solution is enantiomerically enriched relative to the amine compound present in the crystallization solution prior to crystallization.

25. The method of claim 22 , wherein the amine compound in the crystallization solution is racemic.

26. The method of claim 22 , wherein the amine compound in the crystallization solution is enantiomerically enriched.

27. The method of claim 22 , wherein preparing the crystallization solution comprises:

preparing a precursor solution comprising the amine compound, a second enantiomer of the amine compound, and a second enantiomer of the carboxylic acid compound;

crystallizing from the precursor solution the salt of the second enantiomer of the amine compound with the second enantiomer of the carboxylic acid compound, thereby forming the crystallization solution as the supernatant.