Stereospecific synthesis of specifically deuterated metoprolol enantiomers from chiral starting materials

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Abstract
Enantiomers of metoprolol (1) containing six deuterium atoms in the isopropyl methyl groups [(2R‐2], two deuterium atoms at C‐2 and C‐6 of the aromatic ring [(2S)‐3], and two deuterium atoms at C‐3 of the propanolamine side chain [(2S)‐4] were prepared. Chiral 2,2‐dimethyl‐1,3‐dioxolane‐4‐methanols [(4R)‐5 and (4S)‐5] were key synthons. Sources of deuterium were [2H6]‐isopropylamine, 4‐(2‐methoxyethyl)‐2,6‐[2H2]‐phenol (12), prepared by 2HCl/2H2O exchange, and (4S)‐2,2‐dimethyl‐1,3‐dioxolane‐4‐[2H2]‐4‐methanol (19), prepared by LiAl2H4 reduction of (4S)‐methyl 2,2‐dimethyl‐1,3‐dioxolane‐4‐carboxylate. Enantiomeric excess was greater than 94% for each of the prepared enantiomers, as determined independently by 1H NMR spectroscopy on diastereomeric derivatives and by chiral column HPLC.