A Simple Organocatalytic Enantioselective Synthesis of Pregabalin

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.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)