‘Absurd’ radical response retains stereochemistry intact

According to natural chemistry dogma, should you generate a radical on a chiral carbon, it’s going to lose its stereochemistry and racemize. But a new cross-coupling reaction that forges bonds between radicals on two sp³ carbons retains the stereochemistry of one of many coupling companions. The transformation offers quick access to chiral molecules, like substituted piperidines and pyrrolidines, that beforehand took multistep syntheses to make (Science 2026, DOI: 10.1126/science.aef6981).

A workforce led by Phil S. Baran, an natural chemist at Scripps Research in California, developed the response, which makes use of a nickel catalyst to generate two transient radicals, one from an enantioenriched sulfonylhydrazide and the opposite from an achiral major or secondary alkyl halide. The response doesn’t use any chiral ligands or directing teams. Instead, the nickel catalyst reacts with the sulfonylhydrazide to make a diazene complicated. This complicated kicks out N₂ and traps the chiral radical in a nickel complicated cage. The chiral radical then reacts with the unconventional from the alkyl halide.

Baran says that if he had proposed this response 5 years in the past, most chemists—together with himself—would have thought it inconceivable. “The rate of a radical racemizing is about the same as the rate of a bond vibration—we’re talking like picosecond timescale here,” he says.

The concept that you would be able to take two completely different radicals and get them to react with each other with out dropping stereochemistry, with out utilizing a chiral ligand, with none facet merchandise, and with a single catalyst orchestrating the whole occasion “is absurd,” Baran says. “But it works.”

The new radical cross-coupling builds off a similar alkyl-aryl cross-coupling reaction that Baran and coworkers revealed final yr (Nature 2025, DOI: 10.1038/s41586-025-09011-0). “The current work takes us up to the next level, which we didn’t think would ever work,” Baran says.

Daniel Weix, who makes a speciality of natural synthesis on the University of Wisconsin–Madison and was not concerned within the work, says, “It’s astounding to me that the radical formation and capture in the cage enables them to preserve the stereochemistry.” There’s precedent for this sort of chemistry, he says, however it’s often noticed in specialised environments, like an enzyme’s lively web site. “That this is happening in solution is remarkable and holds a lot of promise,” Weix says. “As they continue to broaden the scope, this could be extremely powerful.”

Baran notes that there are limitations to the response. It at the moment works finest with cyclic sulfonylhydrazides. When the chemists tried the response on acyclic sulfonylhydrazides, the stereoretention was low. As they additional develop the transformation, Baran says he hopes it would change into routine. “The aspiration for the lab is always the same,” he says. While his workforce needs to develop reactions which can be fascinating and thrilling when first disclosed, “the hope is that maybe in 30 years it will be a really boring reaction because everybody knows it and uses it.”