Phosphoramidates

Phosphoramidates are organophosphorus compounds in which a phosphorus(V) center bears a P=O unit, two ester-type substituents, and one amine-derived substituent bound directly to phosphorus through a P–N bond. The common structural motif is (R'O)2P(=O)NR'2, with dialkyl or diaryl variants, where the NR'2 group is the amide-like substituent.

Preparation of phosphoramidates typically involves reaction of dialkyl or diaryl phosphorochloridates or related phosphorodichloridates with amines under basic conditions to form the P–N bond, sometimes followed by substitution of remaining halides or alcohols. Alternative routes include oxidation of phosphite or phosphoramidite intermediates in the presence of amines. The chosen method often depends on the desired alkoxy or aryloxy substituents and the amine partner.

Properties and reactivity are governed by the phosphoryl group and the P–N bond. The P=O unit confers notable stability, while hydrolysis can cleave the P–N or P–O bonds under strong acidic or basic conditions, yielding phosphoric acid derivatives and amines. Phosphoramidates can act as phosphate transfer reagents and as precursors to other phosphorus-containing functionalities.

Applications are diverse. In organic synthesis, phosphoramidates serve as phosphate donors, intermediates, or protective/activating groups in the construction of complex molecules. In medicinal chemistry, they are used as prodrug moieties to improve cellular uptake and phosphorylation efficiency, a strategy exemplified by the ProTide approach. Notable examples include phosphoramidate prodrugs of nucleoside monophosphates, such as remdesivir and related antiviral agents, where the phosphoramidate fragment enables delivery of the active phosphate species inside cells.