Synthesis of bi- and tricyclic beta-lactam libraries in aqueous medium

Water as a solvent is not only inexpensive and environmentally benign, but may allow good reactivity. The present work focuses on the application of a modified Ugi reaction, i.e. the Ugi four-centre three-component reaction (U-4C-3CR), in aqueous medium to construct beta-lactam libraries. All the attempted reactions could be successfully performed in water. The reaction conditions under which the precipitation process was effective were investigated; no further work-up or purification was necessary. In several cases when less water-soluble beta-amino acids were used, the precipitated products were isolated easily by simple filtration. In other cases, evaporation of the solvent was appropriate for isolation; when the product was crystalline, recrystallization was necessary to obtain the pure final compounds. In water, the yields were higher as compared with the reactions in organic solvents. When bicyclic beta-amino acids and the bulky tert-butyl isocyanide were used as starting materials, noteworthy increases in diastereoselectivity were observed.