4-Phenyl-4-(p-trifluoromethylphenoxy)piperidine (1), a molecule which approximates a superimposition of the enantiomers of fluoxetine (2a and 2b), has been synthesized and found to be somewhat more active than 2a or 2b as an inhibitor of serotonin uptake. Fluoxetine hydrochloride (2) (Prozac, © Eli Lilly Co.) selectively inhibits the uptake of serotonin at synapses of the central nervous system. Racemic fluoxetine is currently used to treat depression, and for other indications including anxiety, alcoholism, chronic pain, obesity, and bulimia. Although the enantiomers of fluoxetine show similar activity as inhibitors of serotonin uptake, it is possible that they may not be equivalent with regard to side effects or therapeutic efficacy. For this reason we recently developed an effective catalytic enantioselective synthesis of (R)-(+)- and (S)-(-)-fluoxetines. In continuation of this work we have investigated the synthesis and biological activity of 4-phenyl-4-(p-trifluoromethylphenoxy)piperidine (1), an achiral molecule which can be derived structurally by a superposition of conformers 2a and 2b of the enantiomers of fluoxetine. 4-Phenyl-4-(p-trifluoromethylphenoxy)piperidine (1) was prepared in three steps from commercially available 1-benzyl-4-piperidone (3). Treatment of 3 with phenyllithium (THF, -78 °C, 30 min) provided the tertiary alcohol 4 in 69% yield (Scheme 1). Arylation of 4 was effected by formation of the copper alkoxide with n-butyllithium, and cuprous chloride in DME, and subsequent reaction with p-iodobenzotrifluoride to give the aryl ether 5 in 33% yield (unoptimized). Reaction of 5 with ethyl chloroformate (THF, 23 °C, 5 h), followed by heating with ethanolic potassium hydroxide at reflux for 24 h selectively removed the N-benzyl protective group in the presence of the benzylic ether to afford 4-phenyl-4-(p-trifluoromethylphenoxy)piperidine (1) in 78% yield. An in vitro assay testing for inhibition of serotonin uptake showed 1 (580 nM) to be slightly more potent than fluoxetine (700 nM) thus providing support for the idea that 2a and 2b may be the binding conformations of the fluoxetines rather than a different conformer determined for 2 in the solid state by X-ray analysis. The solid state conformation of 1 was determined by X-ray analysis (Figure 1). Comparison of the structure of the potent and chiral serotonin uptake inhibitor sertraline (6) with the chiral conformer of 1 shown in Figure 1 indicates a close three-dimensional correspondence. This suggests that the conformer of 1 in Figure 1, rather than the mirror image conformer, is the form which binds to the receptor.