Chemists have created unique three-dimensional molecules known as heteroatom-substituted cage-like structures. These groundbreaking formations are produced by carefully inserting a triatomic unit into the strained ring of a chemical partner. They present promising solutions to significant challenges in drug design by acting as more reliable options compared to traditional flat aromatic rings.
As the name implies, ring-shaped “cage molecules” bear a resemblance to cages, and their three-dimensional configuration offers them enhanced stability over flatter counterparts. This feature makes them appealing to those in drug development, representing a viable alternative to usual molecular rings from aromatic compounds. A research group at the University of Münster in Germany, led by chemist Prof. Frank Glorius, has introduced a novel method to produce heteroatom-substituted 3D molecules, with their findings published in the journal Nature Catalysis. These groundbreaking structures are crafted by skillfully incorporating a triatomic unit into the high-energy strained ring of a reaction partner.
Aromatic rings are flat structures found in organic compounds and are among the most prevalent components in medicines and agrochemicals. However, their stability can be compromised under physiological conditions, which limits the effectiveness of pharmaceutical agents. To tackle this issue, researchers are investigating sophisticated three-dimensional alternatives—cage-like rings that possess greater rigidity and stability. While some 3D substitutes for basic flat rings like benzene (a ring consisting of six carbon atoms) are already developed, creating 3D variations of flat rings that include essential atoms such as nitrogen, oxygen, or sulfur has proven more challenging. These “heteroaromatic” rings are especially widespread in pharmaceuticals.
The breakthrough achieved by the University of Münster team involved the use of bicyclobutane, a notably reactive compound, and initiating the chemical reaction with light energy. “Utilizing a light-responsive catalyst enabled us to accurately insert nitrogen, oxygen, and carbon atoms into this highly reactive bicyclic molecule, allowing us to create a new type of 3D ring,” Prof. Glorius explains. Prior research primarily concentrated on adding carbon atoms to the bicyclobutane structure. In contrast, incorporating heteroatoms like nitrogen or oxygen results in new variations of cage-like 3D rings. “These new rings could act as substitutes for flat heteroaromatic rings in pharmaceutical compounds, thus paving the way for new avenues in drug development,” states Dr. Chetan Chintawar. These synthesized rings are not only stable and adaptable but can also be easily modified, making them valuable components for generating a variety of other cyclic molecules.
The researchers conducted both experimental and computational analyses to grasp the reaction mechanism. They propose that the reaction begins with an electron transfer event, triggered by light from the excited catalyst to the reactants, leading to the formation of the final products.
