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

Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroep inephrines (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 re spective routes. Binding studies of the catecholamines with alpha(1)-, alph a(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-posit ion of (R)-norepinephrine and (R)-epinephrine reduced activity at both alph a(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 bet a(1)- and beta(2)-receptors. The effects of fluorine substitution on the S- isomers were less predictable.