Highly efficient synthesis of enantiomerically pure (S)-2-amino-1,2,2-triphenylethanol.: Development of a new family of ligands for the highly enantioselective catalytic ethylation of aldehydes

The reaction of (S)-triphenylethylene oxide (3) with diisopropoxytitanium(IV) diazide in benzene solution at 70 degrees C takes place readily in a completely regioselective and stereospecific manner to afford (S)-2-azido-1,2,2-triphenylethanol (6). Reduction of the azide by catalytic hydrogenation leads to (S)-2-amino-1,2,2-triphenylethanol (5) that, by N,N-dialkylation with 1,4-dibromobutane, 1,5-dibromopentane, 1,5-dibromo-3-oxapentane, alpha,alpha'- dibromo-o-xylene, and methyl iodide, affords the corresponding (S)-2-dialkylamina-1,2,2-triphenylethanols (7a-e). On the other hand, the reaction of 5 with benzyl bromide or 1-iodobutane takes place as a monoalkylation, leading to the corresponding (S)-2-alkylamino-1,2,2-triphenylethanols (8f,g). The performance of amino alcohols 7a-e as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 94-97% being recorded. The best performing ligands in this family; 7a [(S)-1,2,2-triphenyl-2-(1-pynolidinyl)-ethanol] and 7c [(S)-2-morpholino-1,2,2-triphenylethanol] have been studied in the addition of Et2Zn to a representative family of aldehydes. With 7a, a 96.6% mean ee is recorded for a family of 16 alpha-substituted aldehydes and a 92.8% mean ee for a family of six alpha-unsubstituted aldehydes. With 7c working on the same families of aldehydes, the mean enantioselectivities are 96.8% and 91.8%, respectively.