Light-activated atom swapping

Another atom-swapping reaction has entered the ring.

Yoonsu Park and his team at the Korea Advanced Institute of Science and Technology (KAIST) have devised a light-driven reaction that replaces an oxygen atom with a nitrogen atom (Science 2024, DOI: 10.1126/science.adq6245). Unlike other recent atom-swapping examples, it is catalytic and designed for five-membered aromatic rings rather than six-membered rings.

The ability to alter complex molecules by a single atom at a time would be incredibly useful for medicinal chemistry—it would enable researchers to, for example, test the influence of different heteroatoms on a drug lead’s properties without having to synthesize each variant from scratch.

The goal is to create what Park refers to as pencil-and-eraser chemistry: “erase one atom, then just add another,” Park says. It’s simple on paper, but this type of single-atom skeletal editing is no easy feat. It requires busting up the extremely stable aromatic system, switching around the atoms, and then stitching the molecule back together.

“There is a long wish list of atom swaps that would be valuable,” says Mark Levin of the University of Chicago, who also works on atom-swapping reactions and was not involved in this study. “This method solves a big one, but maybe more importantly, suggests a way to tackle these kinds of heteroatom-heteroatom replacements” that could pave the way for future advances.

Park says he and his team took inspiration from a 1971 paper in which researchers used ultraviolet light to convert furan to N-propylpyrrole in a 3% yield. He wanted to see if modern photochemical techniques could do the same transformation better. And indeed, though the researchers’ initial attempts to replace the oxygen in 3-phenylfuran produced less than 1% of the pyrrole product they wanted, they persisted and ultimately found conditions that resulted in a yield of up to 92%.

The key to the operation was oxidizing the furan ring using a commercially available acridinium photocatalyst and blue light. This light-driven oxidation creates a cation radical and, crucially, disrupts the ring’s aromaticity. Next, a primary amine adds onto the molecule, triggering a rearrangement that temporarily breaks open the ring into a dialdehyde, which then undergoes a ring-closing condensation to form the final pyrrole.

The reaction works well with a variety of furans and amine pieces, including complex drugs and natural products. Levin says he was surprised to see that the strongly oxidizing acridinium is selective for furans and does not touch other easily oxidized functional groups on the molecule, but the photocatalyst’s electron-transfer rate appears to be just right to enable a clean atom swap.

Park says he and his team are working on developing more ways to skeletally edit five-membered rings, and he’s looking forward to sharing those with the world soon.