Kinetic Resolution of Racemic β-Hydroxy Amines by Enantioselective N-Oxide Formation

Article abstract of DOI:10.1021/jo00222a030

A practical and fairly general procedure for the kinetic resolution of β-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 alcohol are then easily separated by trituration or organic/aqueous solvent extractions, and chromatography is avoided.The oxidations are generally run to 60percent conversion and the results for 21 different amino alcohols are given.The enantiomeric excess of the slow reacting (i.e., recovered) enantiomer of the amino alcohol often exceeds 90percent.Among the more interesting substrates are the natural product ubine (95percent ee) (18), N-methylephedrine (95percent ee) (15), N-methylpseudoephedrine (93percent ee) (16), cis-2-(dimethylamino)cyclohexanol (>95percent ee) (13), trans-2-(dimethylamino)cyclohexanol (92percent ee) (12), N-benzylbevantolol (85percent ee) (27), and N-benzylpropranolol (32percent ee) (21).The latter two examples are β-blocker precursors.One of the most important characteristics of this new route to enantiomerically pure β-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 .A study of how the titanium/tartrate ratio, water, catalyst/substrate ratio, and temperature effect this reaction is discussed.