Enantioselective intramolecular 1,3-diamination of acrylates

The enantioselective synthesis of bicyclic dihydrouracil and sulfamide derivatives through an intramolecular 1,3-diamination of acrylates is described. The method relies on the cyclization of urea and bis-sulfamide substrates, bearing a remote conjugated p-nitrophenyl ester, in the presence of a chiral isothiourea catalyst and diphenyl phosphate as an acid additive, affording the corresponding bicyclic products in good yields (up to 97%) and with excellent enantioselectivities (typically 94:6-97:3, up to 99.5:0.5 er). The transformation proceeds through a tandem intramolecular aza-Michael addition/ lactamisation sequence, with the latter releasing the catalyst and closing the catalytic cycle. Covalent activation of the acrylate through the formation of an acyl ammonium intermediate, combined with non-covalent interactions that facilitate nucleophilic attack and organize the reactive species, provides a plausible basis for the high levels of stereocontrol observed. This metal- and oxidant-free approach overcomes the low electrophilicity of acrylates and shows that nitrogen nucleophiles can participate in isothiourea catalysis.