17123-83-0Relevant articles and documents
Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation
Lundberg, Helena,Tinnis, Fredrik,Zhang, Jiji,Algarra, Andrés G.,Himo, Fahmi,Adolfsson, Hans
, p. 2286 - 2295 (2017)
The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η2-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.
Efficient and accessible silane-mediated direct amide coupling of carboxylic acids and amines
D'Amaral, Melissa C.,Jamkhou, Nick,Adler, Marc J.
supporting information, p. 288 - 295 (2021/01/28)
A straightforward method for the direct synthesis of amides from amines and carboxylic acids without exclusion of air or moisture using diphenylsilane with N-methylpyrrolidine has been developed. Various amides are made efficiently, and broad functional group compatibility is shown through a Glorius robustness study. A gram-scale synthesis demonstrates the scalability of this method. This journal is
Structure–activity relationships (SARs) of α- ketothioamides as inhibitors of phosphoglycerate dehydrogenase (PHGDH)
Spillier, Quentin,Ravez, Séverine,Unterlass, Judith,Corbet, Cyril,Degavre, Charline,Feron, Olivier,Frédérick, Rapha?l
, (2020/02/11)
For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.
