Practical and Selective Syntheses of S‐Acyl and N‐Acyl Glutathiones with N‐Acyl Imidazoles in Water

A selective, mild, convenient, and green protocol for the preparation of S-acyl and N-acyl glutathiones is described involving the chemical modification of glutathione (GSH) with N-acyl imidazoles at room temperature in water. The syntheses of S-acyl glutathiones were achieved in very high yields using 1 equiv of an N-acyl imidazole in water at room temperature, without the need of a base. Double acylation of GSH with various N-acyl imidazoles in weakly basic aqueous media in the presence of N-hydroxysuccinimide (HOSu) as the activating reagent followed by selective deprotection of the S-acyl group with aqueous ammonia at room temperature gave high yields of N-acyl glutathiones. Moreover, the reaction could accommodate a diverse range of carboxylic acids such as (hetero)benzoic acids, phenylacetic acids, aliphatic acids from short-chain fatty acids (including acetic acid), long-chain polyunsaturated fatty acids, secondary or tertiary amino acids, and carboxylic acids containing clickable functional groups, fluorescent probes, or drugs.