Reactivity of amino acid nucleoside phosphoramidates: a mechanistic quantum chemical study

Recent experimental evidence (Maiti et al. Chem.-Eur. J., submitted) indicates that hydrolysis of nucleoside phosphoramidates is subjected to anchimeric influence by carboxyl moieties in the leaving group but also by the base in the nucleotide. A quantum chemical analysis of these findings is presented. First the intrinsic hydrolysis mechanism is investigated for simplified model compounds, and then both amino acid and nucleoside substituents are included. It is found that hydrolysis is assisted by the α-carboxyl group via formation of a five-membered intermediate and that the barrier for the reaction of this intermediate toward the product state can be influenced by the nucleobase. The adenine base protonated on N3 interacts with the transition state and considerably lowers the barrier for hydrolysis. The influence of several base modifications is explained by calculating the pK(a) for protonation on N3.