Synthetic organic chemists love their cross-coupling reactions, in which they quickly construct a complex compound by connecting two different, simpler structures. Building bonds of this type between two sp3 carbons has been a hot area of research, particularly if it can be done in a way that makes the new molecule as a single stereoisomer. Chemists report a new alkyl-alkyl cross-coupling reaction that keeps the stereochemistry of one of the coupling partners intact through what the research team behind it describes as a “metallo-Curtius” mechanism (Nature 2026, DOI: 10.1038/s41586-026-10800-4).
Most stereoselective alkyl-alkyl cross-coupling reactions proceed via a radical intermediate and use a chiral catalyst to lock in the stereochemistry of the final product, says Daniel J. Weix, a chemistry professor at the University of Wisconsin–Madison who led the development of the new reaction along with Bin Wu at Suzhou Novartis Technical Development. Although there is a recent report of an exception, couplings that proceed via radicals tend to lose stereochemistry. “You’re throwing away any chiral information that might have been in your starting material,” Weix says.
The new reaction builds on a nickel-catalyzed alkyl-alkyl cross-coupling reaction that Weix’s lab reported in 2024 (Science, DOI: 10.1126/science.abi4860). The new version starts with a chiral carboxylic acid derivative that the chemists couple with an alkyl iodide. In coupling these two molecules, the reaction generates carbon monoxide.
Weix says students of organic chemistry will recognize the transformation as a variation of the Curtius rearrangement. A typical Curtius rearrangement converts α-chiral carboxylic acids to α-chiral amines, with the α-carbon in an acyl nitrene migrating from carbon to nitrogen. In the new reaction, a similar migration occurs from carbon to nickel as carbon monoxide is lost to decarbonylation. The migration is a nonradical process, so the α-carbon’s stereochemistry is preserved.
Gregory C. Fu, who works on enantioselective cross-couplings at the California Institute of Technology and was not involved in the work, says in an email that the reaction provides a useful new tool for synthetic chemists, “given the availability of a wide variety of enantioenriched carboxylic acids that bear an alpha stereocenter.”
Weix says his team is “excited about extending both the coupling partners that we can connect with this chemistry.”
