Novel bifunctional chiral urea and thiourea derivatives as organocatalysts:: Enantioselective nitro-Michael reaction of malonates and diketones

A modular synthesis of novel bifunctional urea and thiourea organocatalysts derived from cheap, easily accessible natural and non-natural amino acids was reported. The generality of the synthesis was demonstrated in the preparation of catalysts 4a-i in three steps from commercially available N-Boc protected αamino acids. The catalytic activity of 4a-i was first evaluated in the reaction of trans β-nitrostyrene 5a with diethyl malonate 6a in the presence of 10 mol % of catalyst at room temperature. Finally, a series of reactions of diethyl malonate with nitroolefins 5a-f bearing different β-substituents promoted by catalysts 4a-c in toluene at -18°C was conducted. Among the tested catalysts, 4a and ent-4a, thioureas derived from L- or D-valine respectively, are the most promising in terms of cost, yield and enantioselectivity.