HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

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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 a-adrenergic agonist and 2-fluoronorepinephrine is a selective b-adrenergic agonist. Because our previous syntheses of FNEs produced racemic material, we have investigated routes to the pure R-enantiomers. Asymmetric aminohydroxylation of fluorostyrene precursors produced enantio-enriched fluorinated phenethanolamines, albeit with modest enantioselectivities. Highly enantioselective carbonyl reductions of fuorinated chloroketone intermediates with chiral boron catalysts (chemzymes), followed by side-chain elaboration, have provided a route to R-FNEs in good yield. Enantioselective cyanohydrin formation catalyzed by chiral salen catalysts, followed by reduction, is a second procedure we have developed. After final isolation and purification, receptor binding of the pure R- and S-isomers will be carried out to assess the effects of stereoisomerism on receptor selectivities. 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 key precursors to the 2S,3R-isomers of fluorinated DOPS using Evans enantioselective aldol strategy. Fluorinated analogs of purine and pyrimidine bases are being prepared as potential P-site phosphodiesterase inhibitors, and as potential NMR probes for DNA structure and function.