Cocatalyst Tag Team

Adding a chiral urea’s embrace to a ring-forming reaction catalyzed by an achiral Brønsted acid renders the process highly enantioselective, chemists at Harvard University have found (Science 2010, 327, 986). The work could inspire a general strategy for using organocatalysts to perform enantioselective transformations on cations. Several teams have already used “cooperative catalysis” that pairs a metal catalyst or organocatalyst with a cocatalyst to achieve selective bond formations. Eric N. Jacobsen and colleagues have now applied that school of thought to a strong acid-catalyzed cycloaddition that forms a heterocyclic motif common in bioactive compounds. On its own, the Brønsted acid reacts with an imine substrate to form a reactive cationic intermediate, leading to a fast but nonselective reaction. But add the chiral urea, and things change, according to the team’s kinetic, spectroscopic, and computational data. The urea interacts with the cation via a network of hydrogen bonds and a π-π interaction. Effectively, this enzymelike strategy slows the reaction and blocks one face of the cation, permitting formation of only one enantiomer, Jacobsen says. The team plans to extend this controlled reactivity to other classes of cations, he adds.