Optical isomers of metaraminol. Synthesis and biological activity

Abstract

Metaraminol2 is a potent catecholamine deplete!' in heart tissue in a number of animal species.3"6 Shore, Busfield, and Alpers7 reported that ( -)metaraminol is rapidly taken up and retained by sympathetic nerve endings, generally with a stoichiometric exchange between metaraminol and norepinephrine. Grout8 demonstrated a significant fall in blood pressure with ( -)-metaraminol in four of six hypertensive patients. Besides an indirect action of norepinephrine release from tissue storage sites, ( -)-metaraminol has been shown to have direct, sympathomimetic action on the effector organ.9 A large variation in the relative direct and indirect vasopressor activity is seen among the four possible stereoisomers of ephedrine in the anesthetized dog with the (1X2/?) and (15,25) isomers exhibiting less direct activity than the (l/?,25) form.10 Thus, it was of interest to prepare the four optical isomers of metaraminol to determine whether any of these retained the potent indirect release-depletion action seen with ( -(-metaraminol (IR.2S) together with a. reduction of the direct sympathomimetic property.Since quantities of both ( -(-metaraminol and the mother liquors from its resolution11 were available to us. we chose to epimerize the benzylic hydroxyl rather than to synthesize and resolve the t It reo isomer. The route chosen (i.e., introduction of a benzylic group prior to hydrolysis, while longer than direct hydrolysis of the oxazoline, permitted the final product to be readily isolated and purified (Scheme I).Our results agree with those of Dirkx12 who assigned the (IR,2S) configuration to (-(-metaraminol on the basis of optical rotory dispersion and lend further support to the utility of coupling constants of the benzylic hydrogen to demonstrate the enjthro or ihreo configuraf 1 1 Deceased May 1908.(2.) a-( l-AminoethyO-m-hydroxvbenzyl alcohol. The ( -}-erythro isomer a< the í -b)-bitartrate is Pressonex® or Aramine*.

Direct chromatographic resolution and isolation of the four stereoisomers of meta‐hydroxyphenylpropanolamine

“…Prior approaches for preparation of the individual MHPA stereoisomers used either fractional recrystallization 17,18 of the diastereomeric salts of tartaric acid (erythro series) or chemical methods 13 (threo series). In our hands, these methods afforded both low product yields and optical purities (as determined by chiral HPLC analysis).…”

Direct chromatographic resolution and isolation of the four stereoisomers ofmeta-hydroxyphenylpropanolamine

“…Prior approaches for preparation of the individual MHPA stereoisomers used either fractional recrystallization 17,18 of the diastereomeric salts of tartaric acid (erythro series) or chemical methods 13 (threo series). In our hands, these methods afforded both low product yields and optical purities (as determined by chiral HPLC analysis).…”

Uncovering Hydroxynitrile Lyase Variants with Promiscuous Diastereoselective Nitroaldolase Activity toward the Highly Stereocontrolled Synthesis of Anti β-Nitroalcohols

“…The stereoselective coupling of 1 with monodeuterated nitroethane CH 3 CHDNO 2 (a D ) displayed anti-selectivity. 1 H NMR analysis revealed the presence of anti C 6 H 5 CH(OD)CD(NO 2 )CH 3 (1 D a D ) and anti C 6 H 5 CH(OD)CH(NO 2 )CH 3 (1 D a) (Figure 7A), while chiral HPLC analysis of the deuterated Henry products confirmed that high stereoselectivity is sustained during the C−C coupling (Figure S89B). In the absence of Y14C, the synthesis of both syn and anti-stereoisomers of 1 D a D and 1 D a is observed in 1 H NMR (Figure 7A), while the presence of all four diastereomers are evident from chiral HPLC (Figure S89D), suggesting the loss of stereoselectivity due to the nonenzymatic reaction.…”