Manganese May Enhance Large-Scale Pharmaceutical Drug Production

Manganese may offer cost-effective alternative in drug development.

Manganese may offer cost-effective alternative in drug development.

It has long been believed by chemists that placing nitrogen into a carbon-hydrogen bond requires a trade-off between catalyst reactivity and selectivity.

However, a new manganese-based catalyst developed by University of Illinois chemists gives researchers both in one effective, low-cost package.

“Nitrogen is ubiquitous in pharmaceuticals and molecules that come from nature that have very potent biological activities,” said M. Christina White, lead researcher and chemistry professor. “The reaction we report allows chemists to take natural products and drug candidates containing alcohols and convert a carbon-hydrogen bond, 3 carbons away from the alcohol, to a nitrogen.

"Reactions that convert carbon-hydrogen bonds to carbon-nitrogen bonds could transform the solubility or biological properties of a molecule and enable accelerated drug discovery.”

Catalysts for reactions based on precious metals, like rhodium, are reactive but are not very selective, meaning they could react in places other than its target.

White’s lab made iron-based catalysts in the past, which are highly selective, inserting the nitrogen in a precise manner. However, these catalysts are less reactive, only reacting with weaker types of bonds.

“It is commonly accepted that reactivity and selectivity will be inversely correlated, particularly when it comes to difficult transformations like carbon-hydrogen bond functionalization,” White said. “It’s like the difference between using a powerwasher and using a dentist’s water pick. As you become more selective, more targeted, you may become less powerful. As you get more forceful and powerful, you lose the ability to be fine-tuned. We have discovered a catalyst that challenges this reactivity-selectivity paradigm.”

While precious metals have long been known for their predictable and controlled chemical reactivity, White and colleagues analyzed the properties of metals found predominantly in Earth’s crust, which are less-documented and considered difficult to tame.

Researchers guessed that manganese may fall somewhere in the middle of the distinct mechanisms of both rhodium-based catalysts and iron-based catalysts, leading to a blending of reactivity and selectivity.

However, they found in actuality that manganese-based catalysts were very reactive, even more so than rhodium, but it still maintained the high degree of selectivity found in iron catalysts.

“What makes this catalyst really special is that it takes the best parts of the two catalyst families that existed and it combines them into one,” said graduate student Jennifer Griffin, co-first author of the paper. “I’ve always thought of reactivity and selectivity in carbon-hydrogen catalysis as two mutually exclusive properties. Now, by looking at these different metals, we find that it doesn’t have to be separate. You can have both.”

Manganese has many more advantages than rhodium and other precious metals as it is 10 million times more prevalent than rhodium, which means utilizing it for large-scale pharmaceutical production is much more cost-effective.

Manganese is also significantly less toxic as it is found in enzymes throughout the body and used as an ingredient in multivitamins.

This suggests that any pharmaceuticals or compounds made with the catalyst can have higher concentrations of the catalyst left in it, with less need for costly and lengthy purification.

“It really showcases the importance of exploring these types of metals in hopes of replacing precious metals that are more expensive,” Griffin said. “It’s exciting, looking forward to what other kinds of catalysts can be developed for other types of processes.”

Scientists hope that the combination of high reactivity and high selectivity will be a boon to other chemists working to identify and synthesize new drug candidates.

A small change to the molecule’s structure or functionality by adding nitrogen or another functional group in a position that wasn’t accessible before could significantly change the way that molecule works in the body, affecting how it reacts with other molecules or its solubility.

“In the area of medicinal chemistry, you can image that with a very selective, reactive catalyst you can put nitrogen into various sites on a molecule, which opens up a whole new area of functionality to explore,” said co-author Jinpeng Zhao. “It changes the way people can modify bioactive molecules and gives new possibilities of adding function to molecules found in nature.”

For instance, White’s team demonstrated its ability to alter drug candidates by chemically modifying a potential antibiotic molecule, dihydroplueromutilone, combining its previously developed iron catalyst to insert oxygen and the new manganese catalyst to insert nitrogen.

Researchers plan to continue with the exploration of earth metals for catalyzing other reactions at carbon-hydrogen bonds, with studies opening the door to more opportunities for drug development.

Researchers also plan to examine other manganese-based catalyst systems to develop intermolecular reactions that do not rely on having a nearby alcohol group.

“Ultimately our goal is to develop a suite of highly reactive and selective catalysts that enable you to precisely add oxygen, nitrogen and carbon to every type of carbon-hydrogen bond in a complex molecule setting,” White said.