An enantioselective synthesis of S-(+)-fluoxetine (Prozac)

Abstract

An enantioselective synthesis of S-(+)-fluoxetine (Prozac) will be presented. Asymmetry is induced in the achiral starting material, trans-cinnamaldehyde, by the action of the almond enzyme (R)-oxynitrilase in >99% ee. The product (R,E)-2-hydroxy-4-phenylbut-3-enenitrile is then converted to the corresponding alpha hydroxy ethyl ester by hydrolytic esterification. Conversion of the allylic hydroxy group to the ethyl carbonate sets the stage for a palladium-catalyzed 1,3-substitutive chiral transfer reaction with 4-(trifluoromethyl)phenoxytrimethylsilane. Exposure of the allylic carbonate to a palladium(0) catalyst causes the backside displacement of the carbonate group and the concomitant generation of a putative pi-allylpalladium complex. The jettisoned carbonate anion then decomposes to carbon dioxide and ethoxide, which drives the reaction to completion. A substitution reaction between ethoxide and the phenoxytrimethylsilane produces the nucleophilic 4-(trifluoromethyl)phenoxide ion which attacks the distal end of the pi-allyl system opposite the metal to form (S,E)-ethyl 4-(4-(trifluoromethyl)phenoxy)-4-phenylbut-2-enoate. Subsequent reduction of the double bond with hydrogen and Adam?s catalyst followed by amidation of the ethyl ester affords the saturated amide. A Hoffman rearrangement is performed anhydrously in ethanol to form ethyl (S)-3-(4-(trifluoromethyl)phenoxy)-3-phenylpropylcarbamate. Reduction of the carbamate yields the desired S-(+)-fluoxetine.