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An Enantioselective Synthesis of
a Single Enantiomer of Prozac;
Preparation of (S)-(+)-Fluoxetine An enantioselective synthesis of S-(+)-Fluoxetine 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 hydroxy group is converted to the ethyl carbonate. Using a palladium(0) catalyst, the carbonate group is displaced and a 4-(trifluoromethyl)phenoxy group is installed 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-(+)-Fluoxetine as the hydrochloride salt. Current work has shown proof of concept in our synthetic strategy with an optimized enantiomeric excess of 93%. Future work will encompass further investigations into the viability of the aryloxy type nucleophile in the 1,3 substitutive chiral transfer reaction on several allylic carbonates. Support provided by: American Chemical Society-Petroleum Research Fund Grant to Professor Deardorff |
