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Issue 44, 2013
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Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides – a key step in the synthesis of pregabalin

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Abstract

Asymmetric organocatalytic 1,4-additions provide access to a large number of biologically relevant compounds. Chiral squaramides efficiently catalyse enantioselective Michael addition of 1,3-dicarbonyl compounds to aliphatic nitroalkenes. The resulting γ-nitro carboxylic derivatives were obtained in high yields and in high enantiomeric purities. Quantum chemical calculations helped us to devise a transition state model, which explains the observed stereochemical course of the addition. The best results were obtained with Meldrum's acid as a donor, with which enantiomeric purity of the Michael adduct was 97 : 3 e.r. Using this methodology pregabalin was synthesized in three steps in overall 52% yield.

Graphical abstract: Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides – a key step in the synthesis of pregabalin

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Publication details

The article was received on 21 Aug 2013, accepted on 20 Sep 2013 and first published on 24 Sep 2013


Article type: Paper
DOI: 10.1039/C3OB41709C
Citation: Org. Biomol. Chem., 2013,11, 7705-7711
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    Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides – a key step in the synthesis of pregabalin

    R. Baran, E. Veverková, A. Škvorcová and R. Šebesta, Org. Biomol. Chem., 2013, 11, 7705
    DOI: 10.1039/C3OB41709C

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