Chemists develop new method for inserting rings into rings

Many drugs currently available in the market are composed of cyclic (ring-shaped) molecules, often containing multiple rings. Chemists face the ongoing challenge of developing efficient methods for constructing important and novel ring systems, with the aim of producing drugs more effectively and enabling the discovery of new drug structures.

One increasingly popular approach is to modify ring systems through a process known as structural editing. This involves making slight alterations to the molecular framework of compounds at a later stage of synthesis, similar to proofreading and correcting errors in a text.

A team of international chemists, led by Professors Frank Glorius from the University of Münster and Kendall N. Houk from the University of California, Los Angeles, has achieved a significant breakthrough using this method. They successfully inserted a four-membered molecular ring into a larger aromatic ring, creating a structurally complex bicyclic ring system. The team published their innovative strategy in the journal Science.

“We are amazed by the change we achieved in the original ring system. The insertion of a ring within a ring could serve as a blueprint for further advancements,” remarks Frank Glorius. Dr. Huamin Wang, the first author of the paper from the Münster group, adds, “The simplicity and mild reaction conditions of this method also hold promise for potential applications.”

To perform structural editing, it is necessary to selectively cleave at least one chemical bond in the molecular backbone. Visible-light photocatalysis, a modern tool that offers both the energy and selectivity required, was employed by the research team. Specifically, they utilized photoredox catalysis.

The chemical conversion: a four-membered molecular ring (bicyclobutane, BCB) is inserted into a larger ring (thiophene), which is also aromatic. This results in a structurally complex bicyclic ring system. (top: schematic representation; bottom: chemical formulas). Credit: University of Münster—Glorius research group

This particular branch of photocatalysis relies on the transfer of individual electrons. During this process, a photocatalyst absorbs light energy and transfers an electron, thus “activating” the substrate and making it reactive. The use of visible light and photochemical activation enables the development of mild and straightforward reaction conditions.

In the case of the study, the chemists chose to work with thiophene, an important molecule containing sulfur, as the substrate. Through the new process, the carbon-sulfur bond of the thiophene is eventually cleaved. Simultaneously, a strained four-membered ring molecule (bicyclobutane) is inserted between the sulfur and carbon. The conversion is environmentally friendly and atom-economical, ensuring that all the atoms from the starting materials end up in the final product.

To understand the underlying mechanism of this novel reaction, the team adopted a collaborative approach involving experimental and computational chemistry. Professor Frank Glorius’ group conducted a series of experimental studies to investigate the potential mechanisms involved. Concurrently, Professor Ken Houk and his group employed computational modeling to provide detailed insights into the reaction.

Through their combined efforts, the team successfully elucidated how these reactions occur and why they exhibit high selectivity. “Density Functional Theory calculations demonstrated that the photoredox-induced radical-ion mechanisms govern the photoinduced ring expansion processes of thiophene and benzothiophene,” explains Dr. Huiling Shao, a postdoctoral researcher involved in the study.

Source: University of Münster

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