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Preparation of Amines: Reductive Amination of Aldehydes and Ketones

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A Rapid Synthesis Method for Au, Pd, and Pt Aerogels Via Direct Solution-Based Reduction

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Direct Asymmetric Reductive Amination for the Synthesis of (

Guorui Gao¹, Shaozhi Du², Yang Yang³

¹College 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. gaoguorui2001@163.com.

Molecules (Basel, Switzerland)

|September 12, 2018

Summary

This study presents a four-step synthesis of (S)-rivastigmine using direct asymmetric reductive amination. The efficient method yields the drug with high enantioselectivity, crucial for its therapeutic application.

Keywords:

Alzheimer’s syndrome asymmetric catalysis asymmetric reductive amination phosphoramidite ligands rivastigmine

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Area of Science:

Organic Chemistry
Medicinal Chemistry
Asymmetric Synthesis

Background:

Rivastigmine is a key drug for treating Alzheimer's disease.
Efficient and enantioselective synthesis of rivastigmine is crucial for its therapeutic application.

Purpose of the Study:

To develop a novel, efficient, and enantioselective asymmetric total synthesis of (S)-rivastigmine.
To utilize direct asymmetric reductive amination as the key transformation.

Main Methods:

The synthesis employed a four-step route starting from m-hydroxyacetophenone.
Key steps included esterification, direct asymmetric reductive amination using an iridium-phosphoramidite catalyst, N-diphenylmethyl deprotection, and reductive amination.
The asymmetric reductive amination involved coupling 3-acetylphenyl ethyl(methyl)carbamate with diphenylmethanamine.

Main Results:

The synthesis achieved an overall yield of 82% for (S)-rivastigmine.
The key asymmetric reductive amination step provided the chiral amine product with 96% enantioselectivity (ee) and 93% yield.
The final product, (S)-rivastigmine, was obtained with 96% enantioselectivity.

Conclusions:

A highly efficient and enantioselective four-step total synthesis of (S)-rivastigmine has been successfully demonstrated.
Direct asymmetric reductive amination is a powerful key transformation for accessing chiral amines like (S)-rivastigmine.
The developed route offers a practical approach using readily available starting materials.