Enzyme‐Labile Protecting Groups in Peptide Synthesis: Development of Glucose‐ and Galactose‐Derived Urethanes

The development of the tetra‐ O ‐acetyl‐ D ‐glucopyranosyloxycarbonyl (AGlOC) and tetra‐ O ‐acetyl‐β‐ D ‐galactopyranosyloxycarbonyl (AGalOC) protecting groups, which are fully enzyme‐labile, carbohydrate‐derived urethanes, is described. The protected amino acids were easily synthesized and subsequently converted into a series of model dipeptides through classical peptide couplings. Cleavage of an α/β‐anomeric mixture of a model AGlOC dipeptide was achieved with a “one‐pot” procedure in good yield. To gain a better understanding of the enzymatic deprotection reaction, the AGalOC group was removed through a two step biotransformation (lipase catalyzed deacetylation, followed by β‐galactosidase catalyzed glycosidic bond fragmentation). Under these very mild reaction conditions (aq. buffer pH 7.0, 37 °C), the desired N‐terminal, unprotected dipeptide conjugates were obtained. The methodology was further utilized for the synthesis of an advanced tetrapeptide model system.