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International audience; The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

International audience; 5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1′-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.

International audience; Mechanochemistry was effective for the preparation of 3,5-disubstituted hydantoins from a-amino methyl esters, using either 1,1 0-carbonyldiimidazole (CDI) or alkyl isocyanates. The preparation of the antimicrobial additives, 3-allyl-5,5 0-dimethyl hydantoin (ADMH) and 1-chloro-3-ethyl-5,5 0-dimethyl hydantoin (CEDMH) were performed by grinding. A chlorination reaction, never described before by mechanochemistry was achieved by Ca(ClO) 2 , while the preparation of the bioactive anticonvulsant marketed drug ethotoin was achieved by a novel approach based on poly(ethylene) glycol (PEGs) assisted grinding.

International audience; An eco-friendly methodology for preparing Fmoc-, Z-, and Boc-Nprotected dipeptides and tripeptides is described, from the corresponding Nprotected-α-aminoacyl benzotriazoles and α-amino acid derivatives, with different Cterminal functionalities such as esters or amides, using vibrational ball-mill (VBM). The reactivity of a β-amino ester was also investigated. In some cases, the coupling was achieved by liquid-assisted grinding (LAG). α,αand one α,β-dipeptide were obtained in good to excellent yields mainly by precipitation in water, resulting in an improved environmental impact compared to classical peptide synthesis in solution, as shown by green metric calculations. The method was extended to the biotinylation, via an aminohexanoyl spacer, of the pentapeptide RGDfV, which contains the well-known integrins recognition site arginine−glycine−aspartic acid (RGD) motif.

International audience; Mechanochemical derivatizations of N- or Cprotected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.

International audience; 1,1′-Carbonyldiimidazole (CDI) was used as an eco-friendly acylation agent for the mechanochemical preparation of carbamates. The anticonvulsant N-methyl-O-benzyl carbamate was obtained in a vibrational ball-mill, while planetary ball-mill was suitable to develop a new sustainable method to access N-protected amino esters with no racemization. Compared to the synthesis in solution, mechanochemistry proved to be a powerful tool enhancing the reactivity of both alcohol and carbamoyl-imidazole intermediate, under mild conditions, without the need of activation as usually reported for solution synthesis. This new technology provides a sustainable method for the synthesis of carbamates using 1,1′-carbonyldiimidazole.

International audience; The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the “green” synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.

International audience; An eco-friendly methodology for preparing carbamate N-protected α-amino acids is described using ball-milling technology. Some β-amino acids were also investigated in this study. This solvent-free methodology gave Boc-, Z-, and Fmoc-N-protected compounds in good to excellent yields with improved environmental impact compared to classical syntheses in solution. Different planetary ball mills were employed. The results are also discussed according to the different process parameters (grinding material, number of balls, rotation speed).