Stereoselective synthesis of 3‐azido‐2,3‐dideoxy‐D‐ribose derivatives and its utilization for the synthesis of anti‐HIV nucleosides

Abstract

AbstractDetail account of the synthesis of 3′‐azido nucleosides utilizing 3‐azido‐2,3‐dideoxy‐D‐ribose derivative 7 as the key intermediate was described. The key intermediate 7 was synthesized from D‐mannitol in 8 steps in a preparative scale. The Michael reaction of the azide group with α,β‐unsaturated‐γ‐butyrolactone 4 was affected by the steric bulkiness of the substituent at the 5‐O position. A bulky t‐butyldiphenylsilyl substitution at 5‐O gave almost exclusively the α‐azido adduct 5b, while unsubstitution at 5‐O produced 1:1 mixture of α‐and β‐adducts. The ratio of α to β anomers in the condensation between azido acetate 7a and pyrimidine bases for the preparation of AZT and AZDU was greatly influenced by the solvent and the Lewis acid catalyst used. In the synthesis of 12 (AZDU, CS‐87), the combination of dichloroethane and trimethylsilyl triflate gave an optimal result, while in the case of 14 (AZT), various conditions gave similar ratio of α,β anomers. The azido intermediate 7b was also utilized for the synthesis of several 3′‐azido purine‐like nucleosides 16–27. The glycosylation was also affected by the Lewis acid catalyst. Boron trifluoride etherate gave the desired N1‐glycosylated compounds in which the α‐anomer was major, but other catalysts such as trimethylsilyl triflate or stannic chloride produced N2‐glycosylated compounds as the major products. The newly synthesized purine‐like compounds have been tested against HIV, however, none of them showed any significant activity.