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Synthesis

Elegant way to build β-lactams

Palladium-catalyzed process weds aliphatic amines and carbon monoxide

by Bethany Halford
November 18, 2016 | APPEARED IN VOLUME 94, ISSUE 46

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).

Pd-catalyzed reaction makes β-lactams from secondary amines and carbon monoxide.

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.”

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Comments
elcadi (November 19, 2016 7:25 PM)
what's time of reaction
Bethany Halford (November 21, 2016 6:05 AM)
According to the paper's SI, reaction times vary from 3 to 24 hours. The example C&EN shows took 16 hours.
qiong (December 5, 2016 2:23 AM)
are the products racemic?
Bethany Halford (December 11, 2016 7:20 PM)
Yes, all products are racemic.

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