CHEMISTRY
Researchers step closer to mimicking nature’s mastery of chemistry
New approach to synthesis of chiral organic molecules
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CHEMISTS AT UC DAVIS ARE USING CATALYSTS (SHOWN IN GRAY SPHERES) TO MAKE ORGANIC COMPOUNDS (BLUE STICKS) WITH A SPECIFIC CHIRALITY, OR “HANDEDNESS.” MOST BIOLOGICAL MOLECULES ARE CHIRAL, INCLUDING MANY PRESCRIPTION DRUGS. THE DISCOVERY COULD MAKE IT EASIER TO SYNTHESIZE PHARMACEUTICALS WITH THE CORRECT SYMMETRY.
view moreCREDIT: WILLIAM DESNOO/UC DAVIS
In nature, organic molecules are either left- or right-handed, but synthesizing molecules with a specific “handedness” in a lab is hard to do. Make a drug or enzyme with the wrong “handedness,” and it just won’t work. Now chemists at the University of California, Davis, are getting closer to mimicking nature’s chemical efficiency through computational modeling and physical experimentation.
In a study appearing Jan. 10 in Nature, Professor Dean Tantillo, graduate students William DeSnoo and Croix Laconsay, and colleagues at the Max Planck Institute in Germany report the successful synthesis of specific chiral, or “handed,” molecules using rearrangements of simple hydrocarbons in the presence of complex organic catalysts. Most biological compounds, including many prescription drugs, are chiral.
Tantillo and colleagues hope the findings will enable scientists to better harness hydrocarbons for a variety of purposes, such as precursors to medicines and materials.
“The novelty of this paper is that this is really the first time, to my knowledge, that someone has been able to get a carbocation shift that makes one of the mirror image products rather than the other with high selectivity,” Tantillo said.
Little balls of grease
In chemistry, chirality is a property that refers to a pair of molecules that share atomic makeup but are mirror images of each other. Like your left and right hands, they can’t be superimposed on each other.
“Synthetic chemists often want to make molecules that come in mirror image forms, but they only want one of them,” Tantillo said. “For example, if you want to make a drug molecule, often you need one of the two chiral forms to bind selectively to a protein or enzyme target.”
Achieving this can be difficult in a lab setting because such molecules, according to Tantillo, are often like “little balls of grease with some positive charge smeared around them.”
The greasy-like nature of these molecules typically makes binding by a chemical catalyst in one orientation over another difficult due to the lack of charged groups for the catalyst to grab on to.
But the researchers found a solution. Using a chiral organic acid, imidodiphosphorimidate, as a catalyst, the team successfully performed rearrangements of achiral alkenyl cycloalkanes, producing chiral molecules of interest called cycloalkenes. Using computational methods, Tantillo and colleagues deduced how the catalyst selectively produces one chiral form over the other.
Similarities to nature
Tantillo said that the resulting reaction is similar to how enzymes that make hydrocarbon products called terpenes behave in nature. Part of Tantillo’s research concerns mapping terpene reaction pathways using quantum mechanical methods.
“If there are multiple possible pathways to a product, then every time you stop at an intermediate on that pathway, you have the possibility to get byproducts that come from that intermediate,” he said. “So it is important to know when and why a carbocation wants to stop en route to a given terpene if one wants to understand and ultimately re-engineer terpene-forming enzymes.”
The new method published in Nature could in principle be harnessed to produce both natural molecules and nonnatural molecules.
“Whether these things will ever be done is hard to say, but petroleum is a source of a lot of hydrocarbons, and if you could catalytically turn those into molecules with defined chirality, you’ve increased the value of those molecules,” Tantillo said.
Additional co-authors are: Vijay Wakchaure, Markus Leutzsch and Benjamin List, Max Planck Institut für Kohlenforschung, Mülheim an der Ruhr, Germany; and Nobuya Tsuji, Hokkaido University, Sapporo, Japan.
The work was supported in part by the Max Planck Society, the Deutsche Forschungsgemeinschaft and the European Research Council, and the U.S. National Science Foundation.
JOURNAL
Nature
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Not applicable
ARTICLE TITLE
Catalytic asymmetric cationic shifts of aliphatic hydrocarbons
ARTICLE PUBLICATION DATE
10-Jan-2024
COI STATEMENT
A patent on the synthesis of imino-imidodiphosphates catalysts has been filed (patent no. WO 2017/037141 A1, EP 3 138 845 A1). Furthermore, a patent on an improved synthesis of imidodiphosphoryl-derived catalysts using hexachlorophosphazonium salts has been filed (patent no. EP 3 981 775 A1).
Cheap substitute for expensive metal in an industrially common chemical reaction
Researchers from Osaka University and collaborating partners have developed an economical catalyst for an important chemical transformation, which might inspire additional efforts at lowering costs in the chemical industry
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(A) THE PHOTO OF NANO-NI3C/AL2O3 CATALYST. (B) TRANSMISSION ELECTRON MICROSCOPE IMAGE OF NANO-NI3C/AL2O3. (C) HYDROGENATION OF NITRILE TO BENZYLAMINE USING NANO-NI3C OR NI NANOPARTICLE CATALYST, AND THE SUBSTRATE SCOPE FOR THE NITRILE HYDROGENATION CATALYZED BY NANO-NI3C/AL2O3.
view moreCREDIT: 2024 YAMAGUCHI ET AL., NICKEL CARBIDE NANOPARTICLE CATALYST FOR SELECTIVE HYDROGENATION OF NITRILES TO PRIMARY AMINES, CHEMISTRY – A EUROPEAN JOURNAL
Osaka, Japan – The chemical industry commonly uses rare, expensive metals to produce pharmaceuticals and other essential substances. Replacing these metals whenever possible with more-abundant, cheaper substitutes would benefit environmental sustainability, lower costs, and minimize the risk of supply chain disruptions.
Now, in a study recently published in Chemistry – A European Journal, researchers from Osaka University and collaborating partners have met this need in their work on an industrially useful chemical transformation. The simple, gentle reaction conditions reported here might inspire researchers who are working to reduce use of expensive metals for as many chemical reactions as possible.
So-called noble metals are especially versatile materials. For example, palladium is a metal of choice for catalyzing a chemical transformation – converting nitriles into primary amines – that is a common step in nylon and plastics production. However, such metals are rare and costly. Substitutes based on common metals such as nickel could be cheaper catalysts. Unfortunately, many cheap metals require challenging experimental conditions, such as high pressures and temperatures, for the previously mentioned chemical transformation. Determining whether nickel carbide has the same limitations – and if not, evaluating the scope of the chemical transformations that are possible with this catalyst – was the goal of the research team’s study.
“In our work, we thoroughly study the reaction chemistry that underlies a novel nickel carbide nanoparticle heterogeneous catalyst for selective hydrogenation of nitriles into primary amines,” explains Sho Yamaguchi, lead author of the study. “The substrate scope is broad – many types of heteroaromatic and aliphatic nitriles can undergo this transformation.”
There are several advantages of the researchers’ catalyst. One, despite the mild required reaction conditions – 1 atmosphere pressure of hydrogen and a relatively low temperature of approximately 150°C – the catalyst still exhibited 4-times the activity of simple nickel nanoparticles. Two, the catalyst was reusable: at least 3-times. Three, the reaction yields were high: up to 99%.
“We’re excited because our research will help minimize the use of expensive metals for and simplifies the experimental setup of a common class of chemical syntheses,” says Tomoo Mizugaki, senior author. “Furthermore, our theoretical calculations provide insights that will help us optimize the catalyst for additional applications.”
This work is an important step forward in increasing the sustainability of a class of chemical reactions that are required for synthesizing pharmaceuticals and many other everyday products. Because the nickel catalyst is much cheaper than a noble metal, and the required experimental procedures are simple, feasible applications to further chemical transformations should be straightforward.
Hydrogenation of various nitriles using the nano-Ni3C/Al2O3 catalyst under 1 bar H2.
CREDIT
2024 Yamaguchi et al., Nickel Carbide Nanoparticle Catalyst for Selective Hydrogenation of Nitriles to Primary Amines, Chemistry – A European Journal
The article, “Nickel carbide nanoparticle catalyst for selective hydrogenation of nitriles to primary amines,” was published in Chemistry – A European Journal at DOI: https://doi.org/10.1002/chem.202303573
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en
JOURNAL
Chemistry - A European Journal
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Lab-produced tissue samples
ARTICLE TITLE
Nickel Carbide Nanoparticle Catalyst for Selective Hydrogenation of Nitriles to Primary Amines
ARTICLE PUBLICATION DATE
5-Jan-2024
NIH-funded UC research to study copper effects on kidney cancer
High levels of copper tied to worse patient outcomes
Grant and Award AnnouncementIMAGE:
MARIA CZYZYK-KRZESKA, MD, PHD.
view moreCREDIT: PHOTO/UNIVERSITY OF CINCINNATI.
Copper is an essential trace element required to produce energy in the body and allows humans to live in our atmosphere. But research has found that increased accumulation of copper is associated with worse outcomes for patients with the most common type of kidney cancer called clear cell renal cell carcinoma (ccRCC).
The University of Cincinnati Cancer Center’s Maria Czyzyk-Krzeska, MD, PhD, has been awarded a five-year, $2.8 million grant from the National Institutes of Health to investigate how copper contributes to the advancement and recurrence of ccRCC.
Study background
Tobacco smoking is a risk factor for ccRCC. Czyzyk-Krzeska and collaborators, analyzing patient samples from UC, the Cincinnati VA Medical Center and the National Cancer Institute’s Urology Oncology branch, discovered that tumors from patients who were smokers had significantly higher levels of copper compared to nonsmokers. Follow-up studies
using several separate groups of patients showed increased copper accumulation in more advanced tumors and tumors that came back following surgical removal.
“That indicated to us that copper has a potential driving effect in tumor progression of clear cell renal cell carcinoma,” said Czyzyk-Krzeska, a University of Cincinnati Cancer Center researcher and professor in the Department of Cancer Biology in UC’s College of Medicine.
Study details
Czyzyk-Krzeska said the first aim of the study will seek to identify the mechanisms that allow ccRCC cells to take up more copper. The research team will also learn more about copper’s metabolic effects on the tumor cells, specifically the role it plays in the metabolism of mitochondria, the parts of the cell responsible for producing energy.
The third aim of the study will test whether any of the copper-specific features of the tumor cells have vulnerabilities that can open up new treatments for ccRCC.
“There are essentially two or three major lines of treatment for kidney cancer, but ultimately there’s always a group of tumors that are not responsive or recur” said Czyzyk-Krzeska. “We hope what we find is going to provide opportunities for new treatments.”
The data from the study may also shed light on the potential of copper as a biomarker for ccRCC, Czyzyk-Krzeska said.
“Because these levels of copper are higher in certain tumors, we think that copper could be used as a biomarker for evaluation of prognosis and potentially also for predicting which treatment could be appropriate for this specific group of tumors,” she said. “We think that this data will be important for personalized medicine in the treatment of ccRCC.”
Czyzyk-Krzeska said the ongoing research is a multidisciplinary effort between cancer biologists in her department including Tom Cunningham, David Plas and Krushna Patra; UC bioinformatics expert Jarek Meller; and former UC faculty member and analytical chemist Julio Landero, now at Icahn School of Medicine at Mount Sinai New York. The team also collaborates with urologic oncologists, urologists and pathologists at UC.
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