Researchers from MIT and the University of Michigan have found a new method to stimulate chemical reactions that could produce a variety of compounds with valuable pharmaceutical properties.
Azetidines are compounds characterized by four-membered rings containing nitrogen. Unlike five-membered nitrogen-containing rings present in many FDA-approved drugs, azetidines have been historically challenging to synthesize.
By utilizing a photocatalyst to drive the reaction, the researchers were able to predict compounds that can interact to form azetidines using computational models they developed.
Heather Kulik, an associate professor at MIT, mentions that this new method avoids trial-and-error by prescreening compounds to determine which substrates will work effectively.
Kulik and Corinna Schindler from the University of Michigan spearhead the study published in Science, with Emily Wearing as the lead author. Other contributors include Yu-Cheng Yeh and Seren Parikh from the University of Michigan, Gianmarco Terrones from MIT, and Ilia Kevlishvili from MIT.
Light-driven synthesis
Naturally occurring molecules such as vitamins, enzymes, and hormones consist of five-membered nitrogen-containing rings, known as nitrogen heterocycles, prevalent in many FDA-approved drugs. Unlike these, four-membered nitrogen heterocycles (azetidines) are not as common in nature but possess great potential as drug compounds.
Schindler’s lab has been working on using light to drive a reaction combining an alkene and an oxime to synthesize azetidines. This process requires a photocatalyst that absorbs light and transfers energy to the reactions to proceed.
Kulik explains that by transferring energy to molecules, the catalyst drives them into excited states, increasing their reactivity and enabling reactions that might not occur otherwise.
The success of the reaction using a photocatalyst depends on the frontier orbital energy match between the reactants. By calculating the orbital energy of the outermost electrons using density functional theory, Kulik and her team could predict which reactants are likely to form azetidines under photocatalyzed conditions based on their energy levels.
The computational model accurately predicted the reactions of 18 alkene-oxime pairs to form azetidines based on the frontier orbital energies calculated for 16 alkenes and nine oximes.
The study also considered the availability of carbon atoms in oximes to participate in reactions, influencing the overall yield of the reaction.
Kulik emphasizes that this computational approach offers a wider range of possible substrates for azetidine synthesis, increasing accessibility to previously thought challenging reactions.
The researchers tested 18 reactions experimentally, confirming the accuracy of most predictions. Among the synthesized compounds were variations of FDA-approved drugs like amoxapine and indomethacin.
This method can assist pharmaceutical companies in predicting molecules that can react to form valuable compounds, saving resources on unsuccessful synthesis attempts. Kulik and Schindler continue their collaboration on innovative syntheses beyond azetidines.
Kulik believes that using photocatalysts to excite substrates will continue to play a crucial role in synthesizing challenging molecules, expanding its applications significantly.
