New method for producing innovative 3D molecules

Research team at the University of Münster synthesizes three-dimensional ring structures as a possible alternative to biologically active flat rings

Their shape is reminiscent of a cage, and this three-dimensional structure makes them significantly more stable than related flat molecules. Ring-shaped "cage molecules" are therefore a possible alternative to conventional molecular rings from the group of aromatic compounds and are of interest for drug development. A research team at the University of Münster led by chemist Frank Glorius has developed a new method for producing so-called heteroatom-substituted 3D molecules and published it in the journal "Nature Catalysis". The innovative structures are created by precisely inserting a triatomic unit into a strained (high-energy) ring of the reaction partner.

Aromatic rings are flat rings in organic molecules. They are among the most common motifs in pharmaceuticals and agrochemicals. However, these structures can be unstable under physiological conditions and thus impair the efficacy of pharmaceutical compounds. To solve this problem, scientists are researching complex three-dimensional alternatives - cage-like rings that are stiffer and more stable. While such 3D substitutes for simple flat rings such as benzene (a ring with six carbon atoms) are already available, it has been much more difficult to synthesize 3D versions of flat rings that contain one or more other important atoms such as nitrogen, oxygen or sulphur. These heteroaromatic rings are particularly common in drugs with biologically active properties.

The Münster research team’s recipe for success was the use of bicyclobutane, a highly reactive molecule, and the triggering of the chemical reaction with light energy. "By using a light-sensitive catalyst, we were able to precisely insert nitrogen, oxygen and carbon atoms into this very reactive small bicyclic molecule and thus synthesize a new type of 3D ring," describes Frank Glorius. Previous studies had mainly focused on the insertion of carbon atoms into bicyclobutane. In contrast, the insertion of heteroatoms such as nitrogen and/or oxygen leads to new analogs of cage-like 3D rings. "These new rings could potentially serve as a replacement for flat heteroaromatic rings in drug molecules and open up new opportunities for drug development," adds Dr. Chetan Chintawar. The synthesized rings are stable, versatile and can be easily modified, making them useful building blocks for the production of numerous other cyclic molecules.

The researchers carried out experimental and computer-aided studies to understand the mechanism of the reaction. They assume that the reaction begins with the light-induced electron transfer from the excited catalyst to the reacting molecules and then the end products are formed.

The German Research Foundation (DFG), the Alexander von Humboldt Foundation and the German Academic Exchange Service provided financial support for the study.

Original publication

Chetan C. Chintawar, Ranjini Laskar, Debanjan Rana, Felix Schäfer, Nele Van Wyngaerden, Subhabrata Dutta, Constantin G. Daniliuc and Frank Glorius (2024): Photoredox-catalyzed amidyl radical insertion to bicyclo[1.1.0]butanes. Nature Catalysis; DOI: 10.1038/s41929’024 -01239-9