Elegant way to build β-lactams

Abstract

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