CAMBRIDGE, MA: Researchers from the Massachusetts Institute of Technology (MIT) and the University of Michigan have made a significant breakthrough in driving chemical reactions to generate a diverse array of compounds with promising pharmaceutical properties. These compounds, known as azetidines, feature four-membered rings containing nitrogen and have traditionally been challenging to synthesize compared to their five-membered counterparts found in many FDA-approved drugs.
The novel reaction employed by the researchers utilizes a photocatalyst to excite molecules from their ground energy state, enabling the formation of azetidines. By developing computational models, the team was able to predict which compounds would react to form azetidines through this catalytic process.
“Going forward, rather than using a trial-and-error process, people can prescreen compounds and know beforehand which substrates will work and which ones won’t,” said Heather Kulik, an associate professor of chemistry and chemical engineering at MIT.
Kulik and Corinna Schindler, a professor of chemistry at the University of Michigan, are the senior authors of the study published in Science. Emily Wearing, a recent graduate student at the University of Michigan, is the lead author. Other contributors include postdoc Yu-Cheng Yeh, graduate student Seren Parikh from the University of Michigan, and MIT’s graduate student Gianmarco Terrones and postdoc Ilia Kevlishvili.
Light-Driven Synthesis:
Many essential molecules, including vitamins, nucleic acids, enzymes, and hormones, contain five-membered nitrogen-containing rings, or nitrogen heterocycles. These structures are prevalent in over half of all FDA-approved small-molecule drugs, such as antibiotics and cancer therapies. In contrast, four-membered nitrogen heterocycles, although rare in nature, also have potential as drug compounds. However, their synthesis has been notably difficult, limiting their presence in existing pharmaceuticals.
Schindler’s lab has been pioneering the synthesis of azetidines using light-driven reactions involving a photocatalyst, which absorbs light and transfers the energy to reactants, facilitating their reaction.
“The catalyst can transfer that energy to another molecule, moving the molecules into excited states and making them more reactive. This tool is gaining popularity for enabling reactions that wouldn’t normally occur,” Kulik explained.
Despite some successes, the reaction’s efficiency varied depending on the reactants used. Seeking to predict the reaction outcomes, Kulik, an expert in computational approaches to modeling chemical reactions, joined forces with Schindler.
The researchers hypothesized that the success of a photocatalyzed reaction between an alkene and an oxime depends on the frontier orbital energy match. By using density functional theory, they calculated the orbital energies of the outermost electrons in these molecules, predicting which combinations would react favorably when excited by a photocatalyst.
Accurate Predictions:
The team computed the frontier orbital energies for 16 alkenes and nine oximes, predicting the outcomes of 18 alkene-oxime reactions. These predictions were then experimentally tested, with most proving accurate. The computational model also assessed the carbon atoms’ availability in the oximes to participate in reactions, influencing the overall yield.
Kulik noted, “Based on our model, there’s a much wider range of substrates for this azetidine synthesis than previously thought. People didn’t realize the full potential of this approach.”
Among the synthesized compounds were derivatives of FDA-approved drugs such as amoxapine, an antidepressant, and indomethacin, a pain reliever for arthritis. This computational method could enable pharmaceutical companies to identify viable reactant pairs for new compounds, saving significant resources.
Kulik and Schindler plan to continue their collaboration, exploring other novel syntheses, including compounds with three-membered rings.
“Using photocatalysts to excite substrates is a rapidly growing area because traditional ground state or radical chemistry approaches are becoming exhausted,” Kulik said. “This approach is expected to open new possibilities for synthesizing molecules that are usually considered challenging.”
For more information on this groundbreaking research, visit the official websites of MIT and the University of Michigan.
