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.
RT @McGovernMed: Register now for the Pediatric Neuroscience Symposium at Children's Memorial Hermann Hospital on Saturday, May 4! #McGover…
CHI St. Luke's Health@CHI_StLukes
Our love for #GreaterHouston is at the heart of everything we do. In our mission to create healthier communities, we’re sharing our favorite places to inspire health and happiness in our neighbors: https://t.co/oegrvNAWh9 #WeHeartHouston https://t.co/lO6veLnoku
The mystery of ‘mylk’ drove this Rice alumna coco-nuts! Luckily, a group of freshmen helped this entrepreneur find the right mix for shelf-stable vegan coconut milk. https://t.co/cYPiZxKVqT https://t.co/uIvYfwFJYA
RT @BCMCancerCenter: Did you know you can still sign up for tomorrow's Lunch and Learn with Dr. Andrew Sikora hosted by @TheWomensFund? Be…
In honor of National Autism Awareness Month, Dr. Ruth Ann Luna shares the side of autism you don't see often: https://t.co/UuGS12BGqJ #texaschildrens
Harris Health System@harrishealth
Going through menopause can be a bit like traveling in a new city without a map—or even a clear destination. In fact, you may not even realize you’re there until you’ve passed it. Here's how to better cope with this midlife milestone. https://t.co/6s25Aji4oe https://t.co/YUNpLFz3hh
.@VANatCemeteries Veteran sees duty at 35 locations https://t.co/aFx133klvV #VAntagePoint
Let’s bring to light some surprising habits that could be damaging your skin: https://t.co/7VXEaHA9CT. https://t.co/dioqIgDfHD
Vitiligo, Alopecia Merely Cosmetic? Think Again https://t.co/IrsX5jsoMq
MD Anderson Cancer Center@MDAndersonNews
You don’t need any equipment to do #strengthtraining. Here are our tips for an at-home workout: https://t.co/B6LU00kIH9 @FocusedonHealth #endcancer https://t.co/fjCJ2TuPz5
Running and enjoying treats in moderation are just some of the ways Dr. Christina Weng stays fit. See more of her healthy habits: https://t.co/ttuEhmpRmU #healthy #habits https://t.co/NNehV0jfJD
Join us for season two of @TexasChildrens podcast series, Outcomes! Every day incredible stories occur inside our walls, here are a few of those such stories.--> https://t.co/73SXLUB5Pv (Don't forget to subscribe!) https://t.co/fA7C3hgMgJ
RT @SecWilkie: I had the opportunity to share my command philosophy “Walk the Post" at VHA’s NLC meeting earlier today. I am honored to b…
This could be why your hands are always so cold: https://t.co/T6p3d32EZS
RT @isiahcareyFOX26: Amazing story by the staff at TMC News and edited by our good friend @CindyGeorge https://t.co/KHcTqCVp1h!