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

作者：Guorui Gao, Shaozhi Du, Yang Yang, Lei Xue, Haizhou Huang, Mingxin Chang · 发表于：Molecules · 年份：2018 · DOI：10.3390/molecules23092207 · 被引用次数：20 · 研究领域：Asymmetric Synthesis and Catalysis、Chemical synthesis and alkaloids、Asymmetric Hydrogenation and Catalysis

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.