A pH-dependent cyanate reactivity model: application to preparative N-carbamoylation of amino acids

Recent developments in peptide synthesis have underlined the importance of optimising, on a preparative scale, the N-carbamoylation of amino acids by aqueous cyanate. To this purpose, a theoretical model of aqueous cyanate reactivity was designed. The parameters of the model were evaluated, for various pH and temperatures, from a critical survey of the literature, together with additional experimental data. Computer-simulated kinetics based on this model showed the reaction efficiency to be significantly dependent on pH, and suggested optimum conditions to be moderate temperatures and pH 8.5–9. Discussion of the practical convenience of these theoretical results led us to prefer 40–50 °C and a pH range of 7–8 as reaction conditions, thus maintaining reaction times within a few hours. Various N-carbamoyl amino acids (ureido derivatives of glycine, L-valine, L-alanine, L-leucine, DL-methionine, Ne-trifluoroacetyl-L-lysine, β-alanine) were thus successfully synthesised on the gram to kilogram scales.