Elegant way to build β-lactams

The strained cyclic amides known as β-lac­tams have shown up in the skeletons of many medicinally important molecules, including the antibiotic penicillin and the cardiac drug Zetia (ezetimibe). Chemists at the University of Cambridge have developed a new way (shown) to make this structural motif by using a palladium catalyst to join aliphatic secondary amines and carbon monoxide gas in a process that involves C–H activation followed by carbonylation (Science 2016, DOI: 10.1126/science.aaf9621).

The reaction tolerates a broad range of functional groups and can be used on a molecule that’s fairly complex, says Matthew J. Gaunt, who led the research effort. “Amines occur in most drugs, so there’s the potential chemists could use this methodology to perform late-stage C–H functionalization on an already complex molecule,” he says. “I think that could be very powerful for drug discovery.”

Mechanistic studies suggest that the reaction proceeds by a distinct reaction pathway, wherein a putative palladium anhydride forms. A carboxylate ligand on the palladium helps guide the secondary amine to attack the anhydride complex so that a carbamoyl-palladium species forms. C–H activation then leads to a five-membered ring containing nitrogen and a Pd atom. Finally, reductive elimination of the Pd gives the β-lactam product.

Stephen L. Buchwald, an organic synthesis expert at MIT, notes that, over the years, chemists have come up with many ingenious ways to make β-lactams. Buchwald adds, however, that “the C–H activation-carbonylation method reported by Gaunt and coworkers provides a particularly simple and elegant means of accessing this structural unit.” He says the route “is sure to find a great deal of use in the development of new pharmaceutical agents.”