For the first time we report the optimized hydrogen‐isotope exchange (HIE) conditions for the selective aromatic deuteriation of various sulfonylureas and tertiary sulfonamides, as well as for a ...broad range of secondary sulfonamides. Based on a comprehensive screening of readily available Ir catalysts, the Kerr‐type NHC catalyst 5 proved to be most efficient in the HIE reaction of secondary sulfonamides and sulfonylureas. However, for tertiary sulfonamides, the commercially available Burgess catalyst 6, not yet utilized in HIE reactions, resulted in a much higher incorporation of deuterium. Finally, we tested the new HIE protocol for the labelling of a series of sulfa drugs and adapted the conditions to allow for selective tritium labelling.
Optimized hydrogen‐isotope exchange conditions are reported for the first time for the selective aromatic deuteriation of various sulfonylureas and tertiary sulfonamides, as well as for a wide range of secondary sulfonamides.
In this review the applications of isotopically labeled compounds are discussed and put into the context of their future impact in the life sciences. Especially discussing their use in the pharma and ...crop science industries to follow their fate in the environment, in vivo or in complex matrices to understand the potential harm of new chemical structures and to increase the safety of human society.
The applications of isotopically labeled compounds are discussed and put into the context of future impact in the life science industry.
Enantioselective Carbon Isotope Exchange Doyle, Michael G. J.; Bsharat, Odey; Sib, Anna ...
Journal of the American Chemical Society,
07/2024, Letnik:
146, Številka:
28
Journal Article
Recenzirano
The synthesis of isotopically labeled organic molecules is vital for drug and agrochemical discovery and development. Carbon isotope exchange is emerging as a leading method to generate ...carbon-labeled targets, which are sought over hydrogen-based labels due to their enhanced stability in biological systems. While many bioactive small molecules bear carbon-containing stereocenters, direct enantioselective carbon isotope exchange reactions have not been established. We describe the first example of an enantioselective carbon isotope exchange reaction, where (radio)labeled α-amino acids can be generated from their unlabeled precursors using a stoichiometric chiral aldehyde receptor with isotopically labeled CO2 followed by imine hydrolysis. Many proteinogenic and non-natural derivatives undergo enantioselective labeling, including the late-stage radiolabeling of complex drug targets.
The synthesis of a water‐soluble, phosphine‐pegylated iridium(I) catalyst and its application in hydrogen isotope exchange (HIE) reactions in buffer is reported. The longer polyethylene glycol side ...chains on the phosphine increased the water solubility independently from the pH. HIE reactions of polar substrates in protic solvents were studied. DFT calculations gave further insights into the catalytic processes. The scope and limitation of the pegylated catalyst was studied in HIE reactions of several complex compounds in borax buffer at pH 9 and the best conditions were applied in a tritium experiment with the drug telmisartan.
Pegylated phosphine as water‐soluble ligand in iridium(i) catalyzed hydrogen isotope exchange (HIE) reactions. The new catalyst was studied in HIE reactions in buffers and protic solvents. We found that solvent and pH had a strong impact on the two occurring HIE processes.
An assessment of emerging C–H activation catalysts of the type (COD)Ir(IMes)(PR3)PF6 in the deuteration of N-heterocycles is divulged. Substrate scope, competition experiments and labelling of drug ...type molecules have revealed PR3PPh3 provides a broadly more applicable and widely effective catalyst system compared to other available complexes in the present series.
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For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a ...homogeneous iridium catalyst supported by a bidentate phosphine‐imidazolin‐2‐imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivatives proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chemistry, and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst 1 have been provided utilizing DFT calculations, NMR studies, and X‐ray diffraction analysis.
Mild, selective, and efficient: An efficient iridium‐catalyzed protocol for ortho‐selective iridium‐catalyzed deuteration and tritiation of pharmacologically important phenylacetic acid esters and amides has been developed, which proceeds smoothly despite the formation of unfavorable nonconjugated six‐membered metallacyclic intermediates (see scheme).
We describe the dramatic differences in the synthesis and physiological and pharmacokinetical profiling of two sodium‐glucose cotransporter (SGLT) drug candidates AVE2268 and AVE8887 with very ...similar chemical structures. It is a classic example of how a radioactive study was able to spare resources in preclinical development prior to entering a costly clinical program. It also demonstrated that radioactive compounds can be used to study differences between two very similar compounds in vivo.
Dramatic differences in the synthesis and physiological and pharmacokinetical profiling of two sodium‐glucose cotransporter (SGLT) drug candidates AVE2268 and AVE8887 with very similar chemical structures were observed. Discover a classic example of how a radioactive study can terminate a research program and spare resources.
We describe the dramatic differences in the synthesis and physiological and pharmacokinetical profiling of two sodium-glucose cotransporter (SGLT) drug candidates AVE2268 and AVE8887 with very ...similar chemical structures. It is a classic example of how a radioactive study was able to spare resources in preclinical development prior to entering a costly clinical program. It also demonstrated that radioactive compounds can be used to study differences between two very similar compounds in vivo.
An assessment of the C−H activation catalyst (COD)Ir(IMes)(PPh3)PF6 (COD=1,5‐cyclooctadiene, IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene) in the deuteration of phenyl rings containing ...different functional directing groups is divulged. Competition experiments have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium (I) catalyst. Through DFT calculations the iridium–substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition‐metal‐catalyzed functionalization reactions of complex drug‐type molecules as long as a C−H activation mechanism is involved.
Assessment of an iridium(I) catalyst for C−H activation in the deuteration of phenyl compounds substituted with different functional directing groups is disclosed. Competition experiments and DFT calculations have revealed a clear order of the directing groups in hydrogen isotope exchange reactions.
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