Original title: Science: The simplest fa C isotope labeling method at present Recently, some readers reported that they could not receive our push on time every day, because the Wechat Public Number Platform has recently changed the way of push. In order to avoid similar situations, please set a star for "X-MOL Information" (see the Gif at the end of the article for specific operations). After reading the article, click "Watch" to keep the interactive heat, and you will receive each issue in time. Ask a question first-what reaction steps are required to introduce 13C isotope labeling into the carboxyl group of the drug molecule in the figure below? At the recent Science, Professor Rylan J. Lundgren, from the University of Alberta in Canada, gave a very simple solution-dissolve the raw material in dimethylformamide (DMF), and then put it in a carbon dioxide atmosphere labeled by 13 C (13 CO2). 1 atmosphere), wait a few hours and it's done! Depending on the structure of the substrate, a high purity 13C labeled product can be obtained in high yield even after 1 hour at 20.d egree. C., even if water is present in the DMF solution, as long as it does not exceed 0.01 M. Professor Rylan J. Lundgren (fourth from left, back row), Dr. Duanyang Kong (first article, third from left, back row) and the research team. Image Credit: University of Alberta I just saw this work, and I can't believe it. How does this work? Expand the full text Returning to the original question, regardless of the specific route, the usual approach involves removing the original carboxyl group and then finding a way to introduce a carboxyl group with a carbon source labeled with 13 C. Organic chemists have done a lot of research on both types of reactions. Although carboxyl groups are quite stable under most conditions, in order to decarboxylate, there is the former Kolbe decarboxylation, which has been included in organic chemistry textbooks, and the latter is the recent hot photoredox decarboxylation. The introduction of carboxyl groups often relies on strong nucleophiles or the formation of equivalent reducing agents in situ during the electrochemical process. The huge difference in reaction conditions makes the decarboxylation and carboxylation reactions seem impossible to complete in a "one-pot". However, in nature, decarboxylation and carboxylation reactions have always been completed in "one pot". In principle, if the removal of carboxyl groups to form carbon dioxide and its reverse reaction can occur at the same time to form a chemical equilibrium, then in principle, as long as excess 13C labeled carbon dioxide is added to the reaction system, the chemical equilibrium can be shifted to the direction of forming 13C labeled carboxyl groups. In fact, in recent years, some groups have explored the reversible decarboxylation/carboxylation reactions of simple fatty acids, but the high temperature (280 ℃ -400 ℃) limits their application value. Achieving this process at or near room temperature remains a challenge. Reversible decarboxylation/carboxylation of fatty acids. Image Source: Science In this work, Professor Lundgren's team dissolved potassium 4-cyanophenylacetate (1) in DMF (concentration of 0.1 M) and introduced 13 mL of 13 C-labeled carbon dioxide (1 atmosphere, about 6 equivalents in equivalents, when the concentration of carbon dioxide in DMF is about 0.2 M). By monitoring the reaction, it was found that the isotopic exchange reaction reached equilibrium in about 15 hours at 20 ℃, and the product enriched in 13 C was obtained in 83% yield by simple acid-base extraction. Comparison of CO 2 exchange (red) and MeOH protonation (black) of 1. Image Source: Science Further study found that the countercation of the carboxylate and the type of solvent had an important effect on the reaction. If only carboxylic acid, namely 4-cyanophenylacetic acid, is heated to 70 deg C, there is no obvious reaction; when the countercation is lithium ion and sodium ion, the reaction can be carried out, but the reaction speed is slow. A polar aprotic solvent with a dielectric constant greater than 30 is necessary for the reaction, decarboxylation after extraction ,wiped film evaporator, but small amounts of water (less than 0.01 M) and methanol in the system are also compatible.
These results indicate that the solvated ion pairs can effectively promote the reaction. Study on reaction conditions. Image Source: Science In subsequent substrate extension studies, the researchers found that a series of carboxylate molecules containing adjacent aryl, carbonyl, cyano or sulfonyl groups could undergo reversible decarboxylation/carboxylation reactions. The proportion of labeled products depends strongly on the degree of 13 CO 2 excess (chemical equilibrium). Experiments show that the ratio of 13C label in the product can be as high as 95% (13 CO 2 ~ 50 equivalents). The high conversion rate, coupled with the ease of operation, makes this a very competitive strategy for obtaining 13C-labeled carboxylic acids. The ease of operation also allows the reaction to accommodate more groups, including boronic acids, various halogen atoms, aldehydes, ketones, esters, amides, sulfonyl groups, and some reactive aromatic heterocycles. The compatibility with many functional groups allows this method to be used directly to obtain a variety of 13C-labeled drug molecules as well as important active organic molecules such as amino acids (figure below). Substrate expansion and application. Image Source: Science The researchers found that the time required for the reaction to reach equilibrium in the above substrate expansion and the conversion rate (the proportion of the final labeled product) were related to the ability of the substrate to stabilize anions and had little to do with redox capacity, so they speculated that the reaction should be achieved through direct decarboxylation or enol formation. This seems to contradict the compatibility of the reaction with functional groups such as aldehydes and ketones, but in fact, it should be noted that the concentration of carbon dioxide in the system is quite high (0.2 M), so it can preferentially react with the carbanion formed after decarboxylation. In fact, in the presence of a weak Bronsted acid in a nitrogen atmosphere, decarboxylation and protonation do occur, and the rate is inversely proportional to the acidity of the Bronsted acid, indicating that the capture of carbon dioxide formed in the decarboxylation by the Bronsted acid is the rate-determining step. Under nitrogen atmosphere, the "disproportionation" reaction of raw materials was also observed in the experiment. From the appearance, the carboxyl group of one raw material molecule exchanged with the α-H of another raw material molecule. This shows that under the experimental conditions, the carbanion does have a strong ability to capture carbon dioxide. But this process seems to be irreversible. The researchers also noticed that under the experimental conditions, the H/D exchange rate of α-H was also significantly increased, possibly due to the formation of anhydride intermediates, which increased the acidity of α-H. Mechanism study. Image Source: Science The above mechanism studies inspire researchers to use the nucleophiles generated by this mild decarboxylation reaction to react with aldehydes and ketones (under nitrogen atmosphere) to construct a series of molecules by forming C-C bonds. Reactions with other electrophiles. Image Source: Science To sum up, Professor Lundgren's team has found a reversible decarboxylation/carboxylation reaction under very mild conditions (room temperature or near room temperature, without catalyst, 1 atmosphere), which can achieve efficient 13C labeling of a series of substrate molecules. Moreover, further utilization of this reaction can promote H/D exchange and a wider range of C-C bond formation reactions. It is worth mentioning that this Science was submitted on February 25, 2020, received on June 7, and launched on June 18. And not so long ago, Angew. Chem. There is also an online article about reversible decarboxylation. /carboxylation reaction (submission date is also earlier) [1], the substrate molecule of which is an aromatic substituted cesium acetate. The author believes that, in comparison, the expansion of solvent, temperature and substrate range in Angew's study is slightly narrower than that in Science, and the reaction temperature is a little higher.
Direct reversible decarboxylation from stable organic acids in dimethylformamide solution Duanyang Kong, Patrick J. Moon, Erica K. J. Lui, Odey Bsharat, Rylan J. Lundgren Science, 2020, DOI: 10.1126/science.abb4129 References: 1. Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids. Angew. Chem. Int. Ed .,50l rotovap, 2020, DOI: 10.1002/anie.202002341 https://onlinelibrary.wiley.com/doi/10.1002/anie.202002341 (This article is contributed by Hetangyue) This article copyright belongs to X-MOL (X-mol. Com), declines to reprint without permission! Welcome readers to share to Moments or Weibo! Return to Sohu to see more Responsible Editor:. toptiontech.com