N-ALKYLATION VERSUS O-ALKYLATION OF 2,3'-ANHYDROTHYMIDINE - REACTION OF THE OBTAINED PYRIMIDINIUM SALTS WITH AZIDE ION

Reaction of 5'-O-(thexyldimethylsilyl)anhydrothymidine (1) with O-(mesitylenesulfonyl)hydroxylamine and CH3OTf generates the pyrimidinium salts 3a and 3b which react with azide ion to give the N3-substituted AZT derivatives 4a and 4b, respectively. In contrast, alkylation of 1 with pentyl triflate occurs at both the N3 and 04 positions leading, after treatment with NaN3, to the expected AZT analog 4d and the novel 3-substituted 2,3-dideoxyxylofuranosyl azide 7d. In a further study, the extent to which competing 04-alkylation occurs was found to be sensitive to steric factors, increasing in the order MeOTf < EtOTf < pentyl OTf < i-PrOTf. Formation of the alternate 04-alkylated AZT derivatives 9 via an intramolecular Hilbert-Johnson process was not observed in these reactions. It was demonstrated, however, that reaction of the intermediate O4-alkylated pyridinium salt 6c with Me4NCl does evolve toward the corresponding C-3' chloro compound 14c. Reaction of 1 with the less reactive alkylating agent (EtO)2P(O)CH2OTf is more complicated producing the O-alkylated product 7f and the novel dimer 19.