Stereoselective synthesis of nucleoside monophosphate HepDirect™ prodrugs

Synthesis of HepDirect™ prodrugs of nucleoside monophosphates via phosphorylation with a chiral reagent forms a new asymmetric center at phosphorus and produces two diastereomers. Coupling of chiral phosphoramidite 6 derived from (S)-diol 5 with ara-A followed by oxidation of the intermediate phosphite gave ara-AMP prodrugs 8 (4S,2S isomer) and 9 (4S,2R isomer). Several methods were explored to identify routes for the selective synthesis of each diastereomer. Two successful stereoselective approaches to ara-AMP prodrugs 8 and 9 are described.