Kinetic resolution of racemic .beta.-hydroxy amines by enantioselective N-oxide formation

• Published in: Journal of organic chemistry Vol. 50; no. 22; pp. 4350 - 4360
• Main Authors: Miyano, Sotaro, Lu, Linda D. L, Viti, Steven M, Sharpless, K. Barry
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.11.1985; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Exact sciences and technology; Noncondensed benzenic compounds; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Kinetic control; Aminoalcohol; Enantioselectivity; Aliphatic compound; Saturated compound; Aminoether; Chiral compound; Hydroxyether; Optical resolution; Tertiary amine; Reaction mechanism; Benzenic compound; Oxidation; Amine oxide; Catalyst; Monocyclic compound
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo00222a030

A practical and fairly general procedure for the kinetic resolution of .beta.-hydroxy tertiary amines is described. It involves the selective oxidation of one enantiomer to the N-oxide by using tert-butyl hydroperoxide (TBHP) and a chiral catalyst prepared by mixing 2 parts of titanium isopropoxide (Ti(O-i-Pr)4) and 1.2 parts of either (+)- or (-)-diisopropyl tartrate (DIPT). The product N-oxide and the unreacted amino aclcohol are then easily separated by trituration or organic/aqueous solvent extractions, and chromatography is avoided. The oxidations are generally run to 60% conversion and the reuslts for 21 different amino alcohols are given. The enantiomeric excess of the slow reacting (i.e., recovered) enantiomer of the amino alcohol often exceeds 90%. Among the more interesting substrates are the nautral product ubine (95% ee) (18), N-methylephedrine (95% ee) (15), N-methylpseudoephedrine (93% ee) (16), cis-2-(dimethylamino)cyclohexanol (> 95% ee) (13), trans-2-(dimethylamino)cyclohexanol (92% ee) (12), N-benzylbevantolol (85% ee) (27), and N-benzylpropranolol (32% ee) (21). The latter two examples are .beta.-blocker precursors. One of the most important characteristics of this new route to enantiomerically pure .beta.-hydroxy amines is its predictability. Thus, in all cases examined to date, when using (+)-DIPT the absolute configuration at the carbinol center in the slow reacting enantiomer is always the same [i.e., that related to (R)-N-methylephedrine]. A study of how the titanium/tartrate ratio, water, catalyst/substrate ratio, and temperature effect this reaction is discussed.