Synthesis and beta-adrenergic activities of R-fluoronaphthyloxypropanolamine

Many biogenic amines where an aromatic proton is substituted with fluorine have exhibited pharmacological properties that are dependent on the position of fluorine on the aromatic ring. For example, 6-fluoroepinephrine is selective for alpha-adrenergic receptors whereas the 2-fluoroisomer is selective for beta-receptors. Aryloxypropanolamines are beta-receptor agonists or antagonists, depending on the aryl group and its substituents. We therefore hypothesized that fluorine substitution on the atomatic ring could lead to significant biological effects in this class. A target with fluorine on naphthyl group of a known beta-antagonist was chosen for investigation.

Synthesis of the target compound began with fluoronaphthalene and involved introduction of 4-hydroxy group by Friedel-Crafts acylation followed by Baeyer Villiger oxidation. The side chain was introduced stereoselectively using the chiral synthon (2R)-glycidyl 3-nitrobenzenesulfonate, a Sharpless epoxidation technique. The epoxide was opened with t-butyl amine. HPLC methods were used to characterize %ee of the enantiomer.

The target compound was synthesized in several hundred milligram quantity, and in good yield and high enantiomeric excess, showing practicality of the synthetic scheme. It exhibited potent binding activities on beta-adrenergic receptors, and was found to be two times selective for beta 2-receptors over beta 1.

The current report demonstrates that aromatic fluorine substitution on beta-adrenergic ligands can be achieved, and that such can be used to obtain binding selectivity between beta receptors.