How a classic chemistry trick solves 3D C(sp3)-C(sp3) cross-coupling

Did you know that the 3D shape of a molecule can be the difference between a life-saving medicine and a useless compound? It is all about how carbon atoms connect in space.

Building these precise 3D shapes requires linking single-bonded carbon atoms together. This process, called C(sp3)-C(sp3) cross-coupling, is notoriously difficult to control. Drug designers need these specific three-dimensional structures so molecules can fit into biological targets like keys in a lock.

A new route for C(sp3)-C(sp3) cross-coupling

To solve this, researchers designed a clever workaround inspired by a classic reaction called the Curtius rearrangement. By utilising cheap, abundant starting materials like amino acids, they created a temporary nickel-carbon intermediate.

While this intermediate is unstable and degrades within minutes, the team kept the temperature low (between 22 and 40 °C). This cool environment allowed the nickel to couple with alkyl radicals before the 3D structure could twist out of shape.

This method suggests a new way to build specific molecular arrangements that were previously inaccessible. Whilst currently a laboratory method, this strategy could help chemists organise and build complex drug candidates more efficiently.