A New Way to Simplify the Synthesis of Valuable Precursor for Drugs

The most recent discovery of researchers at the Rice University has given a boost to organic chemists, offering a one-step approach to add nitrogen to compounds for fertilizers, pesticides, drugs, and other products.

According to Rice synthetic organic chemist László Kürti,  the approach, published in the Journal of the American Chemical Society, is a significant step ahead as it speeds up and improves the yield of valuable molecules called alpha-aminoketones.

Ketones are carbon-based compounds present in nature and serve as significant feedstocks for the chemical sector. The primary amino group (NH₂) is a functional group found in several chief chemical products. It consists of two hydrogen atoms and one nitrogen atom. A compound known as a primary alpha-aminoketone is fomed by a ketone when it is functionalized with a primary amino group at the alpha carbon.

It's a good precursor because there's no extra functionalization, like an acyl group, on the NH₂ and it can then be converted to whatever you want. Previously, this was the issue: People would put nitrogen in there with extra functionality, but the further processing necessary to get to a free NH₂ was complicated.

László Kürti, Synthetic Organic Chemist and Associate Professor, Department of Chemistry, Rice University

Zhe Zhou, a postdoctoral scientist, discovered the reaction when he combined a nitrogen source and a silyl enol ether in a common solvent called hexafluoroisopropanol at room temperature, and oberved that it imitated Rubottom oxidation, a well-known method to oxidize enol ethers.

“Oxygen is routinely put into the alpha position,” Kürti said. “But nitrogen, no. We are the first to show this is possible in a large number of substrates, and it's simple. It turns out that the solvent itself catalyzes the reaction.”

Zhou and Qing-Qing Cheng, co-author and postdoctoral scientist, enhanced the technique and then tested it by forming 19 aminoketones, including three synthetic amino acid precursors. “These unnatural amino acids are significant for drug design,” Kürti said. “The enzymatic processes in living organisms are not going to attack them, because they don't fit in the enzymes’ pockets.”

Before we had this process, it wasn’t impossible to make these kinds of structures. It was just very complicated and took many steps. The goal, generally, is to get them by the most direct method possible.

Zhe Zhou, Study Lead Author and Postdoctoral Researcher, Rice University

The synthetic processes, which were previously done by the Kürti lab, eliminated the need for transition metal-based catalysts in the production of amines in order to simplify the common and typically inefficient trial-and-error method involved in formulating new chemical compounds such as drugs. Metal-based catalysts that accelerate amination—the introduction of amine groups to an organic molecule—can also contaminate the product; therefore, the new process eliminates them too.

“Our amination method promises to replace a common three-step process to make alpha-aminoketones, and the yield, comparably, is very good,” Zhou said. “In the standard process, each step cuts the yield, so one-step process is still superior even if the yields are identical, because it takes less time and there's less risk of something going wrong.”

“The last thing you want is to get eight steps from the beginning and then ruin it on the ninth because the conditions are not selective enough,” he said. “Cutting steps is always beneficial in organic synthesis.”

Kürti was pleased to see his social media accounts flooded with congratulations from industrial associates and colleagues upon publication of the paper.

There’s a new trend toward late-stage functionalization, where companies with an existing library of compounds can take 100 of them and perform an additional step to make 100 new compounds. So from an intellectual property perspective, our discovery is a great gift to industry. This really is a gem of a find.

László Kürti, Synthetic Organic Chemist and Associate Professor, Department of Chemistry, Rice University

The study was supported by the National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, and Rice University.