title: Chemical aspects of metoprolol metabolism. Asymmetric synthesis and absolute configuration of the 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanols , the diastereomeric benzylic hydroxylation metabolites.
abstract: Asymmetric synthesis of 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanol (2), the benzylic hydroxylation metabolite of metoprolol (1), is described, and the absolute configurations of the diastereoisomers were assigned. Ketone 3, prepared in a multistep synthesis, was reduced with a complex of (2S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (9) and borane, yielding 2, with a ratio of 82:18 for the diastereomers. The absolute configurations 1'S,2S and 1'S,2R were assigned for the diastereomers formed in excess on the basis of reductions on closely related alkyl phenyl ketones and the circular dichroism spectrum. Derivatization of the 1'-hydroxyl group of oxazolidinone 10 with a chiral Mosher acid chloride and the use of an HPLC procedure to resolve the resulting esters enabled us to determine the metabolic product stereoselectivity for 2. In the presence of the rat liver microsomal fraction, the benzylic hydroxylation of 1 was highly product stereoselective favoring 1'R stereochemistry at the new asymmetric center in racemic 1 and in both enantiomers of 1. Determination of the stereochemistry of 2 will facilitate study of this polymorphically controlled metabolic process.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: H U
authors.initials: HU
authors.lastname: Shetty
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D008401:Gas Chromatography-Mass Spectrometry; D006900:Hydroxylation; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; C054515:3-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-1-(isopropylamino)-2-propanol; D008790:Metoprolol