Melatonin receptor agents: Synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (±)-N-[2-(7-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl)ethyl]acetamide

In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (±)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (−)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2. Chirality 13:199–206, 2001. © 2001 Wiley-Liss, Inc.