The revisited synthesis of tert-butyl pyroglutamate derivatives

Abstract

The very common protection reactions of scaffolds by introduction of Boc or tert-butyl groups on lactams or acids in the pyroglutamic series have been revisited in a green perspective. Particularly, reaction conditions allowing a quantitative yield in substitution of bromine in tert-butyl bromide were discovered for the first time, allowing the synthesis of tert-butyl pyroglutamate 4. This synthesis of tert-butyl ester by nucleophilic substitution, realized without using concentrated perchloric or sulfuric acid, could be of interest for acid sensitive compounds. On the other hand, we demonstrated that non toxic N-methylimidazole and tert-butanol can pleasantly replace the problematic toxic 4-dimethylaminopyridine (DMAP) and dichloromethane utilized for the N-carbamoylation of lactam 4. This environmentally improved route to compound 4 allowed the development of a multi-gram supply of protected N-aminoethyl and N-hydroxyethyl γ-glutamine 1 and 2.