Asymmetric hydrogenation (AH) and direct reductive amination (DRA) are both efficient transformations frequently utilized in industry. Here we combine the asymmetric hydrogenation of prochiral olefins and direct reductive amination of aldehydes in one step using hydrogen gas as the common reductant and a rhodium-Segphos complex as the catalyst. With this strategy, the efficiency for the synthesis of the corresponding chiral amino compounds is significantly improved. The practical application of this synthetic approach is demonstrated by the facile synthesis of chiral 3-phenyltetrahydroquinoline and 3benzylindoline compounds.

Direct asymmetric reductive amination utilizing secondary amines as an efficient tool for one-step construction of tertiary chiral amines.

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.

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

Diphenylmethanamine offers excellent stereocontrol and easy deprotection to provide primary amines in the studied asymmetric reductive amination.