Title

An Enantioselective Synthesis of a Single Enantiomer of Prozac; Preparation of (S)-(+)-Fluoxetine

Authors

Derek Ross

Document Type

Article

Publication Date

2008

Abstract

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.

Advisor

Donald Deardorff

Department

chem

Support

American Chemical Society-Petroleum Research Fund Grant to Professor Deardorff

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