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.
A simple and efficient protocol for the preparation of unprotected nucleoside 5′-H-phosphonates and nucleoside 5′-H-phosphonothioates via a one-step deprotection of suitable precursors with methylamine has been developed. The synthetic utility of the unprotected nucleotide derivatives was demonstrated by converting them under mild conditions to the corresponding nucleoside 5′phosphorothioate and nucleoside 5′-phosphorodithioate monoesters. Factors affecting oxidation of H-phosphonate, H-phosphonothioate, and phosphite derivatives with elemental sulfur are also discussed.
H -Phosphonate diesters undergo transesterification with amino alcohols to afford as primary products the mixed and the symmetrical H-phosphonate esters. Alcohols react similarly but only in the presence of an external base or in a basic solvent. The rate and the course of transesterification strongly depend on the reaction conditions, the reactivity of the H-phosphonate diester used, and the nature of the amino alcohol.
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