New enantioselective catalysts based on chiral amino alcohols

Abstract

Enantioselective catalysts based on chiral amino alcohols and their derivatives demonstrate unique features in asymmetric catalytic reactions because the chiral amino alcohols can be easily obtained through reduction of readily available chiral amino acids. The catalysts based on them have been applied in a large variety of asymmetric reactions such as asymmetric reduction, asymmetric diethylzinc addition, asymmetric trimethylsilylcyanation, asymmetric alkylation, asymmetric aldol reaction, etc. Because of their wide applications, ease of synthesis and recovery, new enantioselective catalysts based on chiral amino alcohols are worth exploring. Several previous studies involved the use of 2-amino-1,2-diphenylethanol and 2-amino-2-phenylethanol as chiral ligands. In this study, the cyclohexyl analogs of these ligands have been sucessfully synthesized by hydrogenating the phenyl rings. Furthermore the properties of these new ligands in asymmetric borane reduction of prochiral ketones and asymmetric conjugate addition of diethylzinc to enones have been studied. The objectives of this project are the design and synthesis of a series of new chiral amino alcohols containing cyclohexyl groups, their reactivity and enantioselectivity are compared with their phenyl counterparts. Although a number of successful catalysts based on the use of chiral oxazaborolidines have been explored which give high e.e.'s (enantioselective excess) for the desired chiral alcohols, few examples focus on the investigation of steric and electronic effects of substituents on them. In this study, the phenyl rings on 2-amino-2-phenylethanol and 2-amino-1,2-diphenylethanol were hydrogenated to 2-amino-2-cyclohexylethanol and 2-amino-1,2-dicyclohexylethanol, respectively. The sterically more demanding cyclohexyl analogs are found to be consistently more effective than their phenyl counterparts (the former with e.e. value up to 94.7% and the biggest difference in e.e. between the former and the latter was 36.5%). Moreover, a supplement of the existing mechanism is proposed. Recently the catalytic asymmetric conjugate addition of organometallic reagents to prochiral enones has been attempted. However the enantioselectivities of these processes are relatively low. In this study, the catalyst derived from N,N-dimethyl-2-amino-1,2-dicyclohexylethanol has been found to give good e.e.'s (up to 86.7% e.e.) for a wide variety of enones. Moreover, the enantioselectivity of this catalyst is significantly better than its phenyl analog (the biggest difference in e.e. between the former and the latter was 48.8%). In conclusion, the modification of two existing chiral amino alcohols has been proved to be successful by hydrogenating their phenyl rings to cyclohexyl rings, this study has furnished the chemistry of using chiral amino alcohols as ligands in asymmetric catalytic reactions.