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Molecules 2018, 23(9), 2207;

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

College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging, Shandong Normal University, 88 Wenhuadong Road, Jinan 250014, China
Shanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling, Shanxi 712100, China
These authors contributed equally to this research.
Authors to whom correspondence should be addressed.
Received: 20 July 2018 / Revised: 25 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
(This article belongs to the Special Issue Stereogenic Centers)
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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. View Full-Text
Keywords: Alzheimer’s syndrome; rivastigmine; asymmetric reductive amination; asymmetric catalysis; phosphoramidite ligands Alzheimer’s syndrome; rivastigmine; asymmetric reductive amination; asymmetric catalysis; phosphoramidite ligands

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Gao, G.; Du, S.; Yang, Y.; Lei, X.; Huang, H.; Chang, M. Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine. Molecules 2018, 23, 2207.

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