Scientists at Scripps Research have developed a new chemical reaction that enables highly reactive molecular fragments to be joined while preserving their three-dimensional structure, a breakthrough that could simplify the design and manufacture of future drug candidates.

Published in Science, the study describes a stereoretentive radical-radical cross-coupling method that uses a nickel catalyst to connect carbon-based fragments without disrupting their original chirality. Maintaining this three-dimensional arrangement is important in drug development because many medicines rely on a specific molecular orientation to interact effectively with biological targets.

The researchers said the approach could provide medicinal chemists with a more straightforward way to build complex molecules while avoiding lengthy synthetic routes or the need for specialised shape-directing catalysts.

The reaction couples sulfonyl hydrazides with alkyl halides to form carbon-carbon bonds while retaining the stereochemistry of the starting materials. According to the team, the method achieved stereoretention of between 80% and 96% across a range of pharmaceutically relevant compounds and was compatible with chemical groups commonly used in medicinal chemistry.

The scientists demonstrated the technique using piperidine and pyrrolidine scaffolds, structures frequently found in drug molecules. In one example, a medicinal chemistry building block previously synthesised through seven separate steps was produced in a single coupling reaction while largely preserving its stereochemistry.

The protocol also proved suitable for gram-scale synthesis and enabled the preparation of molecules containing adjacent chiral centres, expanding its potential utility in pharmaceutical research.

Phil Baran, professor at Scripps Research and senior author of the study, said: “Organic chemistry is fundamentally about forming carbon–carbon bonds, and doing so with control over 3D structure is one of the most important obstacles to overcome.”

He added: “Our approach lets us connect the most reactive pieces and still get precise results.”

The work builds on previous advances in radical-based cross-coupling chemistry and may offer researchers an additional tool for constructing structurally complex small molecules used in drug discovery programmes.

Baran said: “Our goal is to make it easier to build the kinds of molecules that matter in medicine. If we can simplify how those structures are assembled, it changes how chemists approach synthesis from the ground up.”