Abstract # A-13

Fourteen amide derivatives of racemic fluoxetine (Prozac®) were prepared and chromatographed under normal-phase conditions on the (S,S)-Whelk-O I CSP. The results were dramatically influenced by the nature of the introduced substituent. The enantiomers of eight amides resolved. Five of these exhibited S,R elution order, with the highest selectivity ( = 1.35) observed for the strongly pi-acidic 3,5-dinitrobenzoyl amide. Three amides exhibited the reverse R,S order. Two of these had the second and third highest selectivities; these were the strongly pi-basic 1- and 2-naphthyl derivatives. The tree amides with the highest selectivities were also the most strongly retained (highest k₂) among the fourteen amides studied. Since the CSP itself possesses both dinitrophenyl and naphthyl moieties, discrete and competing interaction mechanisms incorporating complementary aromatic attraction are clearly inferred. Yet the situation is not entirely straightforward: aliphatic amides such as acetyl and cyclohexyl also resolved, whereas 4-nitrophenyl and 3,5-dimethoxyphenyl amides did not. The underivatized fluoxetine molecule itself contains two aromatic rings, including a 4-(trifluoromethyl)phenoxy substituent; one or both of these rings may also contribute to retention and chiral discrimination. Regardless of these intriguing mechanistic considerations, this approach affords a simple, flexible and robust strategy for the enantiomeric analysis of fluoxetine.