Doing Ugi Reactions With An Enzyme

The multicomponent Ugi reaction is enormously useful to chemists, in particular for building combinatorial peptide libraries for drug discovery. The reaction is usually carried out with an acid or a metal catalyst. Researchers in Poland are now the first to report that an enzyme can facilitate this one-pot reaction, which builds a dipeptide from an amine, an aldehyde, and an isocyanide (Org. Lett., DOI: 10.1021/ol3033829). Because lipases are promiscuous enzymes, Ryszard Ostaszewski of the Polish Academy of Sciences’ Institute of Organic Chemistry and coworkers reasoned they might be able to mediate the classical condensation reaction. The researchers tried a series of commercial lipases and found that the enzymes produce a variety of dipeptides, some with unnatural amino acids and with yields as high as 75% although with no stereoselectivity. The team also found that toluene, chloroform, and water are good solvents, whereas ethanol, a common solvent used in Ugi reactions, surprisingly produced no product. The researchers suggest that enzymes may likewise be tweaked to perform other useful multicomponent reactions.