Syntheses of (R)- and (S)-2- and 6-Fluoronorepinephrine and (R)- and (S)-2- and 6-Fluoroepinephrine:  Effect of Stereochemistry on Fluorine-Induced Adrenergic Selectivities

Abstract

Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroepinephrines (2) were explored. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining steps of two respective routes. Binding studies of the catecholamines with alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined. The assays confirmed that fluorine substitution had marked effects on the affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors, depending on the position of substitution. Thus, a fluoro substituent at the 2-position of (R)-norepinephrine and (R)-epinephrine reduced activity at both alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)-receptors, while fluorination at the 6-position reduced activity at the beta(1)- and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were less predictable.

α2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

“…The highly selective ␣AR agonist 6-fluoronorepinephrine (6FNE), possesses an approximately 10-and 1000-fold selectivity for ␣ 1 ARs and ␣ 2 ARs, respectively, compared with ␤ARs (Lu et al, 2000). We first examined the effects of 6FNE on burst discharges to corroborate the type of ␣AR action on hippocampal activity observed in our previous studies (Jurgens et al, 2005).…”

Electrochemical and spectroscopic characterisation of amphetamine-like drugs: Application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors

“…Method IV is based on a N-formylation of the primary amine (MDA) with ethyl formate (HCO 2 Et) providing the corresponding formamide intermediate (IVa) which after reduction with lithium aluminium hydride gave the N-methyl compound (MDMA) [34,35] in relative good yields.…”

Synthetic and mechanistic studies on asymmetric cyanohydrin synthesis using a titanium(salen) bimetallic catalyst

“…5 This methodology has been applied to the asymmetric synthesis of fluorinated norepinephrines and fluorinated epinephrines. 6 A closely related vanadium(salen) complex was also found to catalyse the asymmetric addition of trimethylsilyl cyanide to aldehydes. 7 We have shown that complex 1 (and the related vanadium(salen) complex) will catalyse the asymmetric addition of potassium cyanide to an aldehyde in the presence of an anhydride, thus providing an asymmetric synthesis of cyanohydrin esters (Scheme 1).…”