Scope and Limitations of Barbituric and Thiobarbituric Amino Acid Derivatives as Protecting Groups for Solid-Phase Peptide Synthesis: Towards a Green Protecting Group

DMB (Dimethylbarbituric) and DETB (Diethylthiobarbituric) are both barbituric and thiobarbituric acid derivatives respectively, that forms enamines with the N-alpha amine of amino acids. These compounds were found to be stable crystalline solids and show stability in the standard acidic and basic conditions used for solid-phase peptide synthesis (SPPS) strategies. These protecting groups are cleaved by a mild solution of 2 % hydrazine hydrate in DMF and 2 % hydroxylamine in DMF, both at short reaction times. Their use in SPPS showed that DMB-protected amino acids allow the preparation of peptides and therefore could be an alternative to the Fmoc strategy currently used. A further advantage of these protecting groups is that their preparation does not involve the concourse of phosgene derivatives and therefore they could be considered greener protecting groups than the carbamate-based one.

Automated summary

DMB and DETB are derivatives of barbituric and thiobarbituric acid that can form enamines with amino acids in solid-phase peptide synthesis. These compounds are stable and can be easily cleaved with mild solutions, making them a greener alternative to carbamate-based protecting groups.