Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with fluorine substituted at various ring-positions. These ring-fluorinated biogenic amines continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine is a selective beta-adrenergic agonist. Because our previous syntheses of FNEs produced racemic material, we have investigated routes to the pure R-enantiomers. Highly enantioselective carbonyl reductions of fuorinated chloroketone intermediates with chiral boron catalysts (chemzymes), followed by side-chain elaboration, have provided a route to R- and S-FNEs in good yield. Enantioselective cyanohydrin formation catalyzed by chiral salen catalysts, followed by reduction, is a second procedure we have developed. Using this approach, R- and S- of 2- and 6-FNE and 2- and 6-FEPI have been prepared. Receptor binding of these were carried out to assess the effects of stereoisomerism on receptor selectivities. The results confirm that receptor selectivity is dependent on fluorine in the 2- or 6-position together with a benzylic hydroxyl group in the correct R-configuration, even thought the R-enantiomers had no greater net selectivity than the racemic mixtures. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6-fluorodihydroxyphenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. We have prepared the 2S,3R-isomers of 6-fluoro DOPS and 2-fluoro DOPS using Evans enantioselective aldol strategy. Sharpless asymmetric aminohydroxylation procedures are being investigated as more efficient approaches to these compounds. Fluorinated metabolites of 6-fluoro-metatyrosine (FMT) have been prepared and are being used as standards in applications of F-18 labelled FMT in PET studies. 2-And 4-difluoromethylimidazole derivatives have been prepared to study the reactivities of side-chain fluorinated imidazoles. Efforts are directed toward synthesis of new side-chain fluorinated bioimdazles. Collaborative studies on development of enantioselective fluorinating agents continue.
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