Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

Abstract

Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.

Direct asymmetric reductive amination is one of the most efficient methods for obtaining chiral amines. Here the authors show how primary alkyl amines can undergo this transformation in the presence of an iridium catalyst with sterically tuneable chiral phosphoramidite ligands, achieving the synthesis of pharmaceutical compounds.