Efficient Synthesis of Exo-N-carbamoyl Nucleosides: Application to the Synthesis of Phosphoramidate Prodrugs

An efficient protection protocol for the 6-exo-amino group of purine nucleosides with various chloroformates was developed utilizing N-methylimidazole (NMI). The reaction of an exo-N(6)-group of adenosine analogue 1 with alkyl/and aryl chloroformates under optimized conditions provided the N(6)-carbamoyl adenosines (2a-j) in good to excellent yields. The reaction of N(6)-Cbz-protected nucleosides (5a-c) with phenyl phosphoryl chloride (7) using t-BuMgCl followed by catalytic hydrogenation afforded the corresponding phosphoramidate pronucleotides (8a-c) in excellent yield.