HOUSTON – (Feb. 8, 2019) – Rice University scientists have given organic chemists a boost with their latest discovery of a one-step method to add nitrogen to compounds for drugs, pesticides, fertilizers and other products.
Rice synthetic organic chemist László Kürti said the method, reported in the Journal of the American Chemical Society, is a major step forward as it quickens and boosts the yield of valuable molecules known as alpha-aminoketones.
Ketones are carbon-based compounds found in nature and important feedstocks for the chemical industry. The primary amino group (NH2) is a functional group present in many important chemical products. It contains one nitrogen atom and two hydrogen atoms. When a ketone is functionalized with a primary amino group at the alpha carbon, it forms a compound called a primary alpha-aminoketone.
“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,” said Kürti, an associate professor of chemistry. “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.”
Postdoctoral researcher Zhe Zhou discovered the reaction when he mixed a silyl enol ether and a nitrogen source in a common solvent, hexafluoroisopropanol, at room temperature and found that it mimicked Rubottom oxidation, an established technique 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 co-author and postdoctoral researcher Qing-Qing Cheng refined the method and subsequently tested it by making 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,” Zhou said. “It was just very complicated and took many steps. The goal, generally, is to get them by the most direct method possible.”
Earlier synthetic processes by the Kürti lab eliminated the need for transition metal-based catalysts in the manufacture of amines in order to simplify the usual and often inefficient trial-and-error approach involved in making new chemical compounds like drugs. Metal-based catalysts that speed up amination – the introduction of amine groups to an organic molecule — can also contaminate the product, so the new process avoids them as well.
“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 delighted to see his social media accounts light up with congratulations from peers and industrial acquaintances 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,” he said. “So from an intellectual property perspective, our discovery is a great gift to industry. This really is a gem of a find.”
The National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation and Rice University supported the research.
#VAResearchNewsBrief: The American College of Physicians @acpinternists released 4 guidance statements on #breastcancer screening for average-risk women. A researcher from the @VAMinneapolis was part of the guideline committee. @VeteransHealth #VAResearch https://t.co/vR1SDnsteD https://t.co/HHj4DPD7cI
@glenda_webb_ @TeamCJCorrea @astros @OrbitAstros Thanks, Glenda, for sharing this great photo!
The underwater dive memorial, called “Circle of Heroes,” will eventually feature 24 concrete statues representing the men and women in the U.S. Air Force, Army, Coast Guard, Marines and Navy https://t.co/VOvuck7S6s via @MiamiHerald
As researchers work to create therapies to target #AML, safety is one of the critical challenges, according to our Dr. Elias Jabbour: https://t.co/S0Wggy1zlD @TargetedOnc #leusm #endcancer
An afternoon swim is a great way to help your kids stay active during the summer months. Make sure they are safe in the water with these tips from Dr. Katherine Leaming-Van Zandt. https://t.co/pVyiG4Jlk3 #swimming #pediatrics
RT @UTHpromotion: Join @UTexasSPH @ProfKimBaker, DrPH, at the #BlackMaternalHealth Summit in Houston on Aug 29 for #BlackMaternalMentalHeal…
RT @NBTStweets: “We feel an obligation because this has happened in our family…So this is our way to pay it forward…We feel an obligation t…
Take a warm bath 1-2 hours before bedtime to get better sleep, @UTHealth researchers find: https://t.co/Bi53wLDvwU
How our #prehab program is helping patients improve strength, endurance and functional capacity ahead of #cancer treatment: https://t.co/eKBYtRtWN5 @DrNgoHuang #endcancer https://t.co/1YQ2YeRYqA
Our Dr. Farhad Ravandi says combining CAR-Ts and BiTEs could “potentially be very interesting and very effective.” #immunotherapy #endcancer https://t.co/Jo7t9JwP9h
Meet the Army Doctor Who Will Spend Seven Months at the International Space Station https://t.co/0FpePtBHWV via @MilitaryOfficer
CHI St. Luke's Health@CHI_StLukes
Last year, Baylor St. Luke’s became the first in Texas to use the #PulseRider, an innovative device used to treat wide-neck bifurcation aneurysms. And now, our team is one of the first to use WEB, a new device in the treatment of complex #BrainAneurysms: https://t.co/QxomC5ne3w https://t.co/kzOvdKt9zO
Deadly fungal disease may be linked to climate change, study suggests: https://t.co/TKlCyiWWxW
University of Houston@UHouston
RT @Brad_Carpenter: How did I not know this little jewel existed on our @UHouston campus?? Get out and explore your campus today. #CoogLead…
@elephande Thank you for sharing your comment with us. Houston Methodist strives to deliver the highest quality, service and care to all our patients. We would like to discuss this issue with you. Please call 713.441.4100 or visit https://t.co/wPtazimDiv