Chiral Phosphoric Acid Catalysis

Over the past decade, chiral phosphoric acid catalysis has become one of the most rapidly growing fields in asymmetric catalysis. Among the various asymmetric reactions that involve chiral phosphoric acid catalysts, asymmetric reduction of ketimines with organic hydride sources, such as Hantzsch esters, has been extensively studied and become one of the most popular reactions in asymmetric phosphoric acid catalysis. Although a number of examples of the synthesis of chiral amines through chiral phosphoric acid-catalyzed asymmetric reductions of imines have been reported, these transformations have been limited to the synthesis of chiral α-aryl amines via enantioselective reduction of imines derived from alkyl aryl ketones. However,the application of the chiral phosphoric acid-catalyzed asymmetric reductive amination to the synthesis of chiral β-aryl amines has been rarely explored since it might be difficult to predict a well-defined structure between the substrate and a chiral phosphoric acid at transition state presumably due to the fact that imines from benzyl methyl ketones might have several possible structures via tautomerization between imines I and enamines I’ and/or possible E/Z isomerization in the resulting imines I and enamines I’.

Furthermore, most of previous approaches have focused on the preparation of chiral free amines after removal of the protection and there have been no any reports where the protection group were utilized as important scaffolds. Thus, our group has focused on the development of new methods for the synthesis of chiral β-aryl amines via chiral phosphoric acid-catalyzed asymmetric reductive amination of benzyl methyl ketone derivatives using Hantzsch ester as an organic hydride source. Furthermore, the resulting chiral β-aryl amine was attempted to be applied to the synthesis of a series of naphthylisoquinoline alkaloids.