Linear synthesis of chiral cycloSal-pronucleotides

Article abstract of DOI:10.1002/ejoc.201100334

CycloSal-nucleosyl-phosphate triesters are a known class of highly effective nucleotide prodrugs (pronucleotides) of antivirally active nucleoside analogues. Until recently, the synthesis of these compounds always gave diastereoisomeric mixtures. Then, a convergent route for the stereospecific synthesis of cycloSal-triesters was described to give isomerically pure cycloSal-prodrugs for the treatment of viral diseases. Here, the development of a stereoselective synthesis of these pronucleotides using various chiral auxiliaries is described. In contrast to pyrrolidine- or pyrrolidinone derivatives it was found that a thiazolidine derived from valinol fulfilled all three requirements to act as a suitable chiral moiety, allowing: (i) strong chirality transfer, (ii) the formation of separable diastereoisomeric intermediates, and (iii) a suitable leaving group that allows the introduction of the nucleoside analogue (e.g., d4T) in the final step under mild reaction conditions. The title compounds were obtained with very high diastereoisomeric excesses of more than 95%. The development of a stereoselective route to cycloSal-nucleotides of thymidine and d4T based on the use of various chiral auxiliaries is reported. The target chiralphosphates were obtained with very high diastereoisomeric excesses of more than 95%.