Direct Asymmetric Reductive Amination for the Synthesis of ()-Rivastigmine.

In this article we demonstrate how asymmetric total synthesis of ()-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap -hydroxyacetophenone, through esterification, asymmetric reductive amination, -diphenylmethyl deprotection and reductive amination, to provide the final ()-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% and 93% yield.