The catalyst, which will shortly be available to purchase from Sigma-Aldrich, allows a carbon-hydrogen bond to be converted into a carbon nitrogen bond, causing a reaction that could affect drug solubility.
“You can now take a complex molecule like betulinic acid and install a nitrogen atom at a site that you couldn’t before. This will change the molecule’s physical properties – like solubility – and may enhance or alter its biological activity,” lab leader Christina White from the University of Illinois at Urbana-Champaign told this publication.
More reactive than rhodium
The precious metal rhodium was known to be able to catalyse such reactions, but it is more prone to react off-target. The new catalyst is more reactive than such rhodium-based catalysts but maintains perfect selectivity. It compares well to previous iron-based catalyst also developed in White’s lab, except that the new manganese-based catalyst can deal with even the strongest carbon-hydrogen bonds.
White pointed to the molecule dihydropleuromutilone in her paper in Nature Chemistry, a molecule with potent antibiotic activities but which has real issues with solubility. “Installing a nitrogen is going to change its solubility and you may also be able to enhance its biological activity,” White explained.
Nitrogen generally can act as a hydrogen bond donor or acceptor and is a very polar atom, which allows it interact well in aqueous media and have good solubility.
Companies interested in discovering new pharmaceutical products will be interested in the new catalyst, the researchers in Illinois believe.
“Unfortunately a lot of pharmaceutical companies have stopped exploring natural products as potential drug candidates. One big reason is because they are so difficult to modify in substantial ways and their solubilities can be poor,” White said. “This [catalyst] allows you take a complex molecule that exists in nature and fundamentally change its hydrocarbon core, which is extremely significant.”
Manganese is around ten million times more abundant than rhodium, so the new catalyst is more cost-effective and sustainable. Manganese is also present in vitamin pills, so its toxicity is expected to be less than rhodium.
“Dealing with removing manganese after the reaction should be easier because the amount of residual metal acceptable in the drug will be higher than for rhodium,” White explained. “All these things make is use easier and can lower R&D costs, allowing interesting drugs to be developed faster.”
The new catalyst requires the presence of an alcohol on the molecules. Though lots of important natural and man-made molecules have alcohols on them, White’s lab is now working to move beyond this restriction and produce a catalyst that does not require this tether and which could perform hydrogen-carbon amination anywhere on a compound.
Though some metals from the first row of the periodic table can install nitrogen in C-H bonds, they tend to scramble the stereochemistry, whereas the new catalyst does not do so.