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Issue 39, 2013
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Concise asymmetric synthesis of a (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester

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Abstract

The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described. Both compounds are common building blocks in multiple preparations of potent HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of (E)-N-benzylideneglycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated model for the stereo-selectivity that was guided by calculations and rigorous quality control of the starting materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystallization process. A chemical resolution procedure was identified using di-p-toluoyl-(D)-tartaric acid to access (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee.

Graphical abstract: Concise asymmetric synthesis of a (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester

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Publication details

The article was received on 07 Jul 2013, accepted on 14 Aug 2013 and first published on 14 Aug 2013


Article type: Paper
DOI: 10.1039/C3OB41394B
Org. Biomol. Chem., 2013,11, 6796-6805

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    Concise asymmetric synthesis of a (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester

    S. Lou, N. Cuniere, B. Su and L. A. Hobson, Org. Biomol. Chem., 2013, 11, 6796
    DOI: 10.1039/C3OB41394B

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