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Skeletal edit swaps carbon for nitrogen

Single-atom edit offers medicinal chemists a direct route from quinolines to quinazolines

by Mark Peplow, special to C&EN
November 2, 2023


Mark Levin is on a roll. In September, the University of Chicago chemist unveiled a reaction that could replace a carbon atom in an aryl ring with a nitrogen atom—a precision edit to a molecule’s core structure that could prove invaluable for medicinal chemists. Now, Levin and his team have unveiled a different reaction that can perform a C-to-N swap in aromatic molecules that already contain a nitrogen atom, such as quinolines (Nature 2023, DOI: 10.1038/s41586-023-06613-4).

Scheme shows reaction that replaces a carbon atom with a nitrogen atom to develop a belumosudil precursor.

Together, the two methods should enable medicinal chemists to make these single-atom substitutions in a swath of common molecules, easing efforts to generate analogues of drug candidates. “This is the problem that I started my lab to tackle,” Levin says.

The method is the latest entrant to the burgeoning field of skeletal editing, which aims to add, delete, or swap single atoms within a molecule’s backbone. Such alterations can have a profound effect on a molecule’s biological activity, by altering its polarity, solubility, or hydrogen-bonding ability, for example. Swapping out carbon in favor of nitrogen is a common tactic for boosting the potency of pharmaceuticals, but in practice these analogues often need to be made from scratch, necessitating the lengthy effort of an entirely new synthetic sequence.

Levin’s graduate student Jisoo Woo led the work to develop a more direct method for making the crucial atom swap. It builds on a light-driven process developed in 2022 by Levin’s team, which deletes a carbon atom from a ring containing an N-oxide group.

Researchers begin the new method by turning a quinoline into its N-oxide and applying light to trigger a rearrangement. They then deploy ozonolysis to break open a key intermediate and use ammonium carbamate to insert a nitrogen atom, eject a carbon atom, and re-close the ring. These chemical operations can all be done in one pot.

The upshot is that a wide variety of quinolines can be converted to quinazolines in typical yields of about 50–90%. As a proof of principle, the team used the method in a gram-scale synthesis of a precursor of belumosudil, a medicine that can prevent complications after bone marrow transplants.

“I think it’s fantastic. The idea of replacing a carbon with a nitrogen has been sought after in medicinal chemistry for a really long time,” says Richmond Sarpong at the University of California, Berkeley, who works on skeletal editing and was not involved in the research.

The method still has some important drawbacks—the reaction conditions can cause undesirable alterations to alkene and ester groups, for example. “But it does give a pretty broad coverage of medicinally relevant chemical space,” Sarpong says. “Despite the limitations, it’s still a powerful tool to add to the toolbox.”

Levin’s team hopes to make both of its C-to-N swapping reactions more generally applicable, so they can tackle a wider array of aromatic substrates, regardless of their substituents or architecture. “I’m not really going to be satisfied until we can do this on any arene,” Levin says.


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