Radicals meet in cage match

According to organic chemistry dogma, if 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 the coupling partners. The transformation provides easy access to chiral molecules, like substituted piperidines and pyrrolidines, that previously took multistep syntheses to make (Science 2026, DOI: 10.1126/science.aef6981).

A team led by Phil S. Baran, an organic chemist at Scripps Research in California, developed the reaction, which uses a nickel catalyst to generate two transient radicals, one from an enantioenriched sulfonylhydrazide and the other from an achiral primary or secondary alkyl halide. The reaction doesn’t use any chiral ligands or directing groups. Instead, the nickel catalyst reacts with the sulfonylhydrazide to make a diazene complex. This complex kicks out N₂ and traps the chiral radical in a nickel complex cage. The chiral radical then reacts with the radical from the alkyl halide.

Baran says that if he had proposed this reaction 5 years ago, most chemists—including himself—would have thought it impossible. “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 idea that you can take two different radicals and get them to react with one another without losing stereochemistry, without using a chiral ligand, without any side products, and with a single catalyst orchestrating the entire event “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 published last year (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 specializes in organic synthesis at the University of Wisconsin–Madison and was not involved in 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 type of chemistry, he says, but it’s usually observed in specialized environments, like an enzyme’s active 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 reaction. It currently works best with cyclic sulfonylhydrazides. When the chemists tried the reaction on acyclic sulfonylhydrazides, the stereoretention was low. As they further develop the transformation, Baran says he hopes it will become routine. “The aspiration for the lab is always the same,” he says. While his team wants to develop reactions that are interesting and exciting 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.”