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Various approaches to the synthesis of nucleoside H-phosphonamidates have been investigated. Direct couplings of nucleoside H-phosphonates with amines have been hampered by extensive reactions of the condensing agents with amines. Preactivation of nucleoside H-phosphonates with pivaloyl chloride or chlorophosphates, followed by the addition of amines, notably diminished these side reactions. The most efficient and versatile route to nucleoside N-alkyl H-phosphonates was found to be aminolysis of the in situ-produced aryl nucleoside H-phosphonates with appropriate amines.

New synthetic protocol for the preparation of nucleoside 5'-(N-aryl)phosphoramidate monoesters 4 was developed. It consisted of a condensation of the corresponding nucleoside 5'-H-phosphonates with aromatic- or heteroaromatic amines promoted by diphenyl phosphorochloridate, followed by oxidation of the produced H-phosphonamidates with iodine/water. 5'-(N-Aryl)phosphoramidate monoesters derived from 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyuridine (ddU) nucleosides and various aromatic and heteroaromatic amines were evaluated as potential anti-HIV drugs. It was found that these compounds act most likely as pronucleotides and that some of them have therapeutic indices superior to those of the reference AZT.

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The efficiency and stereoselectivity of condensation of ribonucleoside 3 0 -H-phosphonates with alcohols were investigated as a function of amines used for the reaction. It was found that irrespective of the presence or absence of nucleophilic catalysts, the Dynamic Kinetic Asymmetric Transformation (DYKAT) was the major factor responsible for the stereoselective formation of the D P (S P ) isomers of the H-phosphonate diesters, and a mechanistic rationalization of this observation was proposed. In addition, studies on the reactions carried out in the presence of various bases led to the conclusion that certain sterically hindered pyridines, e.g. 2,6-lutidine, may act as nucleophilic catalysts in the condensation of ribonucleoside 3 0 -H-phosphonates with alcohols.