Chemists develop mild 'cut-to-fuse' method to restructure molecules for drug discovery

Chemists face a persistent problem: when they want to redesign a molecule for a new drug, they often have to tear it apart and rebuild it from the ground up. A faster approach exists—skeletal editing, which restructures molecules while keeping much of their existing framework intact. But this technique has hit a wall with certain molecular structures, particularly those containing esters, whose bonds resist breaking under gentle conditions.

A team at Ritsumeikan University, led by Professor Toshifumi Dohi alongside Yusuke Yoto and Dr. Hideyasu China of Doshisha Women's College of Liberal Arts, found an answer by looking to nature. Their work, published in JACS Au in July 2026, describes a method that uses chlorine to trigger a cascade of molecular events: bonds break, a carbonyl group vanishes, and the molecule reassembles itself into a new, useful shape called a coumaranone. The researchers call it a "cut-to-fuse" strategy—chlorine cuts the bonds, then the molecule fuses itself back together in a different configuration.

The discovery came partly by accident. The team had been experimenting with fluorine as a bond-breaking agent in hydroxycoumarins, a class of organic compounds. Fluorine didn't work as hoped; it shattered the molecule into fragments. But when they switched to chlorine, treating the compound with N-chlorosuccinimide, something unexpected happened. Instead of fragmenting, the molecule underwent a controlled transformation, shedding its carbonyl unit and reorganizing into a coumaranone. "Chlorine changed the reaction pathway completely," Dohi observed. The team realized they had stumbled onto something more elegant than they'd anticipated.

What makes this breakthrough practical is its mildness. The optimized reaction runs at room temperature, requires no metal catalysts, and operates in nearly neutral conditions—a combination that represents the gentlest approach yet reported for simultaneously breaking the carbon-carbon and carbon-oxygen bonds involved in this type of carbonyl deletion. When the researchers treated hydroxycoumarins with N-chlorosuccinimide, water, sodium acetate in ethyl acetate, and then potassium phosphate, they achieved yields exceeding 99 percent. The method also proved remarkably flexible. Molecules bearing methoxy groups, halogens, azides, phenols, carboxylic acids, and boron-containing functionalities all survived the reaction intact. Substrates with naphthalene, pyridine, thiophene, furan, and aliphatic groups also worked. Several products emerged in good to excellent yields, demonstrating that the chemistry accommodates substantial structural diversity.

Mechanistic studies confirmed that selective chlorination was the key. When researchers omitted the chlorinating reagent, the starting material remained unchanged. Stepwise experiments revealed the sequence: chlorination first, then decarboxylation, then intramolecular cyclization—a three-step dance that happens in one pot. The team also tested the method at gram scale, obtaining the desired coumaranone in 91 percent yield. The resulting molecules could be further modified through various transformations, including conversion to benzofurans, introduction of quaternary carbon centers, and palladium-catalyzed coupling reactions. One particularly useful variant bore a boron pinacol ester, which could be applied directly in coupling reactions without requiring isolation and purification.

The inspiration for this work came from halogenation-driven transformations observed in natural product biosynthesis—the chemical pathways that living organisms use to build complex molecules. By adapting this principle, the researchers created a route from hydroxycoumarins to coumaranones that avoids the harsh, energy-intensive conditions traditionally required to break ester bonds. For medicinal chemistry, where the ability to rapidly generate and test structurally diverse compounds can accelerate drug discovery, this mild and efficient method opens new possibilities. Rather than spending weeks rebuilding molecules from scratch, chemists can now edit existing scaffolds under conditions gentle enough to preserve delicate functional groups, then quickly test whether the new structures have pharmaceutical promise.