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

1. A compound of Formula:

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 or

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;

Pg is an amine protecting group; and

is a cyclic boronic acid ester; and

wherein the compound has an enantiomeric excess of greater than 75% ee.

2. The compound of claim 1 , wherein the compound is of Formula I:

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 ;

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; and

Pg is an amine protecting group; and

wherein the compound has an enantiomeric excess of greater than 75% ee.

3. The compound of claim 2 , wherein R a is tert-butyl.

4. The compound of claim 2 , wherein R c is H.

5. The compound of claim 4 , wherein R d is acetyl or trifluoroacetyl.

6. The compound of claim 2 , wherein R d is acetyl or trifluoroacetyl.

7. The compound of clam 2 , wherein X is NH.

8. The compound of claim 2 , wherein X is O.

9. The compound of claim 2 , wherein the compound has an enantiomeric excess of between 95% and 99.7% ee.

10. The compound of claim 2 , wherein the compound has an enantiomeric excess of greater than 90% ee.

11. The compound of claim 2 , wherein the compound has an enantiomeric excess of greater than 95% ee.

12. The compound of claim 2 , wherein the compound has an enantiomeric excess of greater than 99% ee.

13. The compound of claim 2 , wherein Pg is formyl, acetyl, trifluoroacetyl, benzyl, methoxymethyl (“MOM”), benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“2-TES”), triethylsilyl (“TES”), triisopropylsilyl (“TIPS”), tert-butyldimethylsilyltrityl (“TBDMS”) and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), or nitro-veratryloxycarbonyl (“NVOC”).

14. The compound of claim 2 , wherein Pg is formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), allyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl (“FMOC”).

15. The compound of claim 2 , wherein the compound is

wherein:

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

R c is H; and

X is O, S, or NR e .

16. The compound of claim 15 , wherein the compound has an enantiomeric excess of greater than 90% ee.

17. The compound of claim 1 , wherein the compound is of Formula II:

wherein:

X is O, S, or NR e ;

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

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;

Pg is an amine protecting group; and

is a cyclic boronic acid ester; and

wherein the compound has an enantiomeric excess of greater than 75% ee.

18. The compound of claim 17 , wherein the cyclic boronic acid ester is a pinacol boronate.

19. The compound of claim 17 , wherein the compound has an enantiomeric excess of greater than 90% ee.

20. The compound of claim 17 , wherein the compound is:

wherein:

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

R c is H; and

X is O, S, or NR e .

21. The compound of claim 20 , wherein the cyclic boronic acid ester is a pinacol ester.

22. The compound of claim 20 , wherein the compound has an enantiomeric excess of greater than 90% ee.

23. A process to prepare a compound of Formula IV:

wherein G is H, methyl, isopropyl, sec-butyl, —CH 2 CH(CH 3 ) 2 , benzyl, p-hydroxybenzyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 -3-indoyl, —CH 2 COOH, —CH 2 CH 2 COOH, —CH 2 C(O)NH 2 , —CH 2 CH 2 C(O)NH 2 , —CH 2 SH, —CH 2 CH 2 SCH 3 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 3 NHC(═NH)NH 2 , or —CH 2 -3-imidazoyl;

said process comprising:

(a) providing a compound of Formula III:

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 ;

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; and

R e is H or lower alkyl; and

wherein the enantiomeric excess of the compound of Formula III is greater than 80% ee;

(b) adding an amine protecting group to the secondary amine of the compound of step (a) to form a compound of Formula I of claim 2 :

wherein Pg is the amine protecting group

(c) subjecting the compound formed in step (b) to hydroboration conditions to form a compound of Formula II of claim 17 :

wherein

is a cyclic boronic acid ester;

(d) subjecting the compound formed in step (c) to conditions sufficient to form the compound of Formula IV;

wherein the compound of Formula IV formed in step (d) has an enantiomeric excess of greater than 80% ee.

24. The process of claim 23 , wherein Pg is formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, methoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyltrityl, trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or nitro-veratryloxycarbonyl.

25. The process of claim 23 , wherein Pg is formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), allyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl (“FMOC”).

26. The process of claim 23 , wherein the cyclic boronic acid ester of the compound of Formula II is a pinacol boronate.

27. The process of claim 23 , wherein the enantiomeric excess of the compound of Formula III is greater than 90% ee.

28. The process of claim 23 , wherein the enantiomeric excess of the compound of Formula III is greater than 95% ee.