An Enantioselective Synthesis of S-(+)-Fluoxitine

Abstract

An enatioselective sythesis of S-(+)-Fluoxitine is shown by utilizing the enzyme (R)-oxynitrilase to induce chirality, in high enantiomeric excess, in trans-cinnamaldehyde to form (R,E)-2-hydroxy-4-phenylbut-3-enenitrile. After converting the nitrile functionality to the ethyl ester thru a hydrolytic esterification, the hydoxy group is converted to the ethyl carbonate. Using tetrakis(triphenylphosphine)palladium(0) as a catalyst, the carbonate group is displaced and a 4-(trifluoromethyl)phenoxy group is instaled in a 1,3 substitutive chiral transfer to form (S,E)-ethyl 4-(4-(trifluoromethyl)phenoxy)-4-phenylbut-2-enoate. After subsequent reduction of the double bond and amidation of the ethyl ester, a Hoffman rearrangement is performed anhydrously in ethanol to form ethyl (S)-3-(4-(trifluoromethyl)phenoxy)-3-phenylpropylcarbamate. Subsequent reduction and treatment with HCl yields S-(+)-Fluoxitine as the hydrochloride salt.