Enantioselective synthesis of optically active secondary amines via asymmetric reduction

Abstract

The enantioselective synthesis of optically active secondary amines via the asymmetric reduction of N-substituted ketimines with various chiral hydride reagents, such as Itsuno's reagent ( 1), Corey's reagent ( 2), K glucoride ( 3), Sharpless' reagent ( 4), and Mosher's reagent ( 5) has been investigated. Among the hydride reagents examined, 1 gave the best results in terms of asymmetric induction. Thus, the reduction of N-phenylimine derivatives of aromatic ketones with 1 provided the corresponding amines in 96–98% yields with high optical induction, such as 73 % ee for acetophenone N-phenylimine ( 6a), 87 % ee for propiophenone N-phenylimine ( 6b), 88 % ee for bulyrophenone N-phenylimine ( 6c), and 71 % ee for isobutyrophenone N-phenylimine ( 6d). In the case of N-alkyl ketimine derivatives, the reduction afforded somewhat lower optical inductions as compared to those of N-phenyl derivatives, giving 46 % ee for acetophenone N-benzylimine ( 6f), 52 % ee for acetophnone N- n-heptylimine ( 6g) and 43 % ee for acetophenone N-cyclohexylimine ( 6h). However, the substitution of a bulky alkyl group on nitrogen of the ketimines increases remarkably the optical induction of product amine, such as 80 % ee for acetophenone N- tert-butylimine (6e). The reduction of N-substituted aliphatic ketimines gave very low optical inductions (7.4 – 24 % ee). The catalytic effects of oxazaborolidines ( 1a and 2a) in the reduction of ketimines with 1 and 2 were also examined.