Process for preparing fluoroleucine alkyl esters

1. A process for preparing a compound of formula I:

wherein R is hydrogen or C 1-6 alkyl;

comprising the steps of:

a. Alkylating an imine of formula II. with a fluorotriflate electrophile to form a substititued imine;

b. Forming an azlactone;

c. Enzymatically opening the azlactone with a hydrolytic enzyme to form an alkyl amide;

d. Deprotecting the alkyl amide with an oxidizing agent to produce the compound of formula I, wherein the hydrolytic enzyme is immobilized lipase B from C. Antarctica , lipase from P. fluorescens , lipase from P. cepacia , lipase A from C. Antarctica , lipase from porcine liver or lipase from P. stutzeri.

2. The process of claim 1 wherein the alkylation is performed in the presence of a strong base.

3. The process of claim 2 wherein the strong base is potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, lithium diisopropylamide, sodium hydride, n-BuLi, sec-BuLi, t-BuLi, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium 2,2,6,6-tetramethylpiperidide.

4. The process of claim 3 wherein the strong base is potassium t-butoxide.

5. The process of claim 1 wherein the azlactone formation is performed with a carbonyl activator.

6. The process of claim 5 wherein the carbonyl activator is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide, acetic anhydride, pivaloyl chloride or 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate.

7. The process of claim 6 wherein the carbonyl activator is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.

8. The process of claim 1 wherein the hydrolytic enzyme is immobilized lipase B from C. Antarctica.

9. The process of claim 1 wherein the oxidizing agent is 1,3-dibromo-5,5-dimethylhydantoin, iodine, bromine, N-bromosuccinimide, N-iodosuccinimide or 1,3-dichloro-5,5-dimethylhydantoin.

10. The process of claim 9 wherein the oxidizing agent is 1,3-dibromo-5,5-dimethylhydantoin.