Computational Modeling Aids Challenging Chemical Synthesis

Researchers from MIT and the University of Michigan have identified a novel approach to drive chemical reactions, enabling the generation of azetidines, compounds with promising pharmaceutical properties. Azetidines are characterized by four-membered rings incorporating nitrogen, which have traditionally posed greater synthetic challenges compared to their five-membered counterparts frequently found in FDA-approved drugs.

The newly discovered reaction is facilitated by a photocatalyst that excites molecules from their ground energy states, allowing them to interact and form azetidines. Utilizing computational models they developed, the researchers successfully predicted which compounds would react to form azetidines under this catalysis. According to Heather Kulik, an associate professor at MIT, this method allows for pre-screening of compounds, eliminating much of the trial-and-error typically associated with such reactions.

The study’s senior authors are Heather Kulik and Corinna Schindler, a University of Michigan chemistry professor, and the lead author is Emily Wearing, a recent University of Michigan graduate. Additional contributors include Yu-Cheng Yeh, a University of Michigan postdoc, Gianmarco Terrones, an MIT graduate student, Seren Parikh, a University of Michigan graduate student, and MIT postdoc Ilia Kevlishvili. Their findings are published in Science.

The synthesis of azetidines is driven by light, a method Schindler's lab has been exploring. This light-driven reaction combines an alkene and an oxime, facilitated by a photocatalyst that absorbs light and transfers energy to the reactants, initiating their interaction. Kulik explains that the catalyst moves molecules into excited states, making them more reactive and capable of undergoing otherwise unlikely reactions.

Schindler's laboratory faced inconsistent results depending on the reactants used, prompting collaboration with Kulik, who specializes in computational modeling of chemical reactions. They hypothesized that the success of the photocatalyzed reaction relies on a property known as the frontier orbital energy match. Quantum mechanics predicts the shapes and energies of the orbitals where electrons reside, and the highest energy (frontier) orbitals are critical for chemical reactions.

Using density functional theory, Kulik and her students calculated the orbital energies of these frontier electrons. These calculations account for other atomic groups attached to the molecule, which influence the electron properties. Once the energy levels were determined, the researchers identified reactants with similar energy levels in their excited states. When these states are closely matched, the reaction requires less energy to reach its transition state and proceed to form products.

The team calculated frontier orbital energies for 16 alkenes and nine oximes, using their computational model to predict whether 18 different alkene-oxime pairs would react to form azetidines. These predictions, made in seconds, suggested some reactions wouldn't occur or would yield insufficient results. Nonetheless, the study showed many of these reactions were correctly predicted to be successful.

Their experimental validation tested 18 reactions, confirming the accuracy of most predictions. Among the synthesized compounds were derivatives of FDA-approved drugs, such as the antidepressant amoxapine and the arthritis pain reliever indomethacin.

This computational approach holds promise for pharmaceutical companies by enabling the prediction of reactive molecules before investing in synthetic processes that may fail. Kulik and Schindler continue to explore novel syntheses, including the formation of compounds with three-membered rings. Kulik highlights the potential of photocatalysts in generating challenging molecules, making this an exciting area of chemical development.