'Cut-to-fuse' strategy: A new route for molecular skeletal editing

'Cut-to-fuse' strategy: A new route for molecular skeletal editing Swati Mestri Scientific Editor Robert Egan Senior Editor Restructuring a molecule without rebuilding it from scratch is an increasingly important goal in modern organic chemistry. Skeletal editing is an approach that helps chemists explore new chemical structures and simplify the synthesis of molecules with potential pharmaceutical applications. But in the case of functional groups such as esters, skeletal editing remains difficult because their carbon–carbon and carbon–oxygen bonds are resistant to cleavage under mild conditions. Now, a research team led by Professor Toshifumi Dohi of Ritsumeikan University, along with Yusuke Yoto, also of Ritsumeikan University, and Dr. Hideyasu China of Doshisha Women's College of Liberal Arts, developed a unique solution inspired by nature. Their study, published in JACS Au on July 26, 2026, demonstrates that introducing chlorine into hydroxycoumarins can trigger a sequence of bond-cleavage and bond-forming events that removes a carbonyl group and reconstructs the molecule as a coumaranone. "We aimed to develop a new way of editing molecular skeletons for esters, one that could break difficult bonds under mild conditions and immediately reconstruct the molecule into a useful framework," Dohi says. From fragmentation to reconstruction The idea started from the team's interest in a "cut-to-fuse" strategy. In this concept, halogenation first "cuts" bonds in a cyclic compound, generating a reactive chain, before a subsequent intramolecular reaction "fuses" the chain into a new heterocyclic structure. The researchers projected that a similar process might enable carbonyl deletion—the net removal of a carbonyl unit from hydroxycoumarins. The initial experiments produced an unexpected result. The team had been investigating fluorine-induced carbon–carbon bond cleavage, but fluorination caused the hydroxycoumarin to fragment into separate products. "Chlorine changed the reaction pathway completely," Dohi says. Treating a hydroxycoumarin with N-chlorosuccinimide (NCS) led to the formation of a chlorinated intermediate that underwent decarbonylative reconstruction, ultimately producing a coumaranone rather than fragmenting the molecule. Mild conditions, high yields The researchers then optimized the reaction and found that the transformation could proceed at room temperature under near-neutral conditions without transition-metal catalysis. Under the optimized conditions, hydroxycoumarin was treated with NCS, water and sodium acetate in ethyl acetate, followed by potassium phosphate. The method produced the model coumaranone in more than 99% yield. According to the researchers, this represents the mildest nonenzymatic conditions reported to date for simultaneous cleavage of the C–C and C–O bonds involved in this type of carbonyl deletion. This reaction also proved broadly applicable. Hydroxycoumarins containing methoxy, halogen, azide, phenol, carboxylic acid and boron-containing functionalities were tolerated, as were substrates bearing substituted aromatic rings, naphthalene, pyridine, thiophene, furan and aliphatic groups. Several products were obtained in good to excellent yields, demonstrating that the method can accommodate considerable structural diversity. A related cyclic β-keto ester also underwent reconstruction, showing that the chemistry is not limited to a single substrate class. Evidence for selective chlorination Mechanistic experiments highlighted the importance of selective chlorination. When the chlorinating reagent was omitted, the starting material was recovered unchanged. Stepwise experiments showed that chlorination occurred first, followed by decarboxylation and intramolecular cyclization. The team also demonstrated the method's practical potential. On a gram scale, the model reaction produced the desired coumaranone in 91% yield. The resulting scaffold could then be further modified, including conversion to a benzofuran, introduction of a quaternary carbon center and transition-metal-catalyzed coupling reactions. In this case, a coumaranone bearing a boron pinacol ester was useful because it could be directly applied in palladium-catalyzed coupling without isolation. A biosynthesis-inspired editing route Taking inspiration from halogenation-driven transformations found in natural product biosynthesis, researchers developed a new way to rethink carbonyl deletion and molecular scaffold construction. Their cut-to-fuse strategy provides an efficient route from hydroxycoumarins to coumaranones while avoiding the harsh conditions usually required for ester bond cleavage. This study could be useful for future approaches in medicinal chemistry, where streamlined molecular editing is increasingly valuable for rapidly generating structurally diverse compounds. Publication details Yusuke Yoto et al, Halogen-Guided Reconstructive Transformation of Hydroxycoumarin to Coumaranone, JACS Au (2026). DOI: 10.1021/jacsau.6c00801 Journal information: JACS Au Provided by Ritsumeikan University