Unusual Radical Coupling Keeps Stereochemistry Unchanged

In line with a widely accepted rule in organic chemistry, a radical formed on a chiral carbon will lose stereochemistry by racemization. A team headed by Scripps Research's Phil S. Baran in California has cast doubt on that by creating a new type of alkyl–alkyl cross-coupling reaction. The reaction allows the preparation of bonds between two sp³ carbon radicals without changing the stereochemistry of one of the coupling partners, thus offering a more straightforward approach to chiral molecules of interest, such as substituted piperidines and pyrrolidines, which were difficult to prepare in multiple steps.

The method uses a nickel catalyst to generate two transient radicals, one from an enantioenriched sulfonylhydrazide and the other from an achiral primary or secondary halide. No chiral ligands or directing groups are needed. Rather, the catalyst undergoes a diazene complex with the sulfonylhydrazide, eliminates N2 gas, and then “cages” the chiral radical, which reacts before the scrambling process.

Even five years ago, most chemists, including Baran, would have deemed such a reaction impossible, since radical racemization is on a picosecond timescale. The stereochemistry-preserving coupling of two radicals, without chiral ligands, with a single catalyst is “absurd,” he said, but it works.

The advance is built on a related alkyl–aryl cross-coupling reaction that Baran's group reported last year. The result was remarkable, said Daniel Weix at the University of Wisconsin–Madison, who has long studied stereochemical control in the synthesis of complex molecules: "Similar stereochemical control is typically only observed in specialized environments like enzyme active sites.

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