HMN 2026: How A new three-way single step rearrangement enables precise ring editing

A new three-way bond-breaking and making mechanism makes the synthesis of five-membered rings easier than before.

In a study published in Science, researchers from Southern University of Science and Technology, China, demonstrate a triatropic rearrangement in which three carbon-carbon single bonds are broken while two new single bonds and one double bond are formed simultaneously, all through a single coordinated transition state.

The process brought together the power of pericyclic reactions, a tool widely used in organic chemistry for designing complex structures, with a simple elimination reaction.

Aided by organoboron and zinc reagents, this unique mechanism lets chemists shrink molecules like six-membered rings into five-membered rings—a transformation that has long frustrated synthetic chemists. The team successfully converted epoxides—a small ring-shaped molecule made of two carbons and one oxygen—into complex structures like cyclopentanes, an organic molecule consisting of a five-carbon ring.

Ring manipulation made easier

Changing the number of carbon atoms in a ring in an organic molecule has the ability to completely change the physical and chemical properties of the molecule. Chemists are always on the lookout for ways to influence how molecules behave, which is why chemists are so interested in making and modifying them.

Over the years, several strategies have been developed, yet ring-shrinking transformations remain a major challenge. Although reactions such as the Favorskii and Wolff rearrangements can achieve this goal, they are often difficult to execute, struggle with complex molecular architecture, and lack stereoselectivity—a property of a chemical reaction that favors the formation of one specific molecule.

To overcome this limitation, the researchers redesigned pericyclic reactions to achieve two goals: reorganize molecular skeletons with high precision and edit complex molecules.

The new chemical route, triatropic rearrangement, was designed by combining the dyotropic rearrangement—a chemical process in which two ?-bonds simultaneously migrate within a single molecule—with an elimination step that provides the extra push needed to drive the reaction forward.

To test their design, the researchers started with epoxides and performed a Diels–Alder reaction to form a six-membered ring foundation. They then opened the epoxide ring using organoboron reagents to form a stable intermediate structure called a cyclic borate. This was followed by the addition of zinc salts, which replaced the boron and triggered the reaction to enough to undergo the final triatropic rearrangement, which yielded a 5-membered ring.

The team named this ring contraction protocol: The “[4+2-1]” Strategy. Using this method, the researchers could edit the core frameworks of complex natural molecules—such as steroids and terpenoids—while achieving 1,2-hydride migrations in linear epoxides.

Mechanistic studies and DFT calculations reveal that this new strategy enables highly chemo-, regio-, and stereoselective ring contraction of epoxides to cyclopentanes and introduces an alkenyl boronic ester lynchpin for further molecular diversification.

The triatropic rearrangement gives chemists a precise new way to build and modify molecules, opening promising paths for faster drug discovery and the development of advanced materials.