A Simple Organocatalytic Enantioselective Synthesis of Pregabalin

Oriol Bassas, Juhani Huuskonen, Kari Rissanen, Ari M.P. Koskinen

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    Abstract

    This paper describes a new procedure for the enantioselective synthesis of the important anticonvulsant drug Pregabalin, which shows biological properties as the (S) enantiomer only. The key step of the synthetic sequence is the Michael
    addition reaction of Meldrum’s acid to a nitroalkene mediated by a quinidine derived thiourea. A variety of novel catalysts bearing different groups at the thiourea moiety were synthesized and tested. The most successful catalyst that incorporates a trityl substituent provided up to 75% ee of (S)-4. The conjugate addition reaction was carried out on a multigram scale with low loadings of catalyst (10 mol-%). Moreover, the catalyst can be recycled showing the same
    capability in chemical yield and asymmetric induction. Then, hydrogenation of nitroalkane 4 followed by decarboxylation of diacid 5 provides Pregabalin hydrochloride in 59% overall yield. Enantioenrichment by crystallization of the free amino acid 1 improves the (S)/(R) enantiomeric ratio to 9:1.
    Original languageEnglish
    Pages (from-to)1340-1351
    JournalEuropean Journal of Organic Chemistry
    Issue number9
    DOIs
    Publication statusPublished - 2009
    MoE publication typeA1 Journal article-refereed

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