Solvent-free organocatalytic Michael addition of diethyl malonate to nitroalkenes: the practical synthesis of Pregabalin and γ-nitrobutyric acid derivatives

A highly enantioselective synthesis of Pregabalin 1 hydrochloride with good overall yield (44%) and enantioselectivity (98% ee) was described. The key step is an asymmetric Michael addition of equivalent of diethyl malonate and nitroalkene under solvent-free conditions using thiourea 2 as catalyst. The reaction can be applied to a variety of aromatic and aliphatic substituted nitroalkenes affording corresponding adducts in good to excellent yields (61–92%) and enantioselectivities (78–93% ee).