STEREOSELECTIVE SYNTHESIS OF 3-AZIDO-2,3-DIDEOXY-D-RIBOSE DERIVATIVESAND ITS UTILIZATION FOR THE SYNTHESIS OF ANTI-HIV NUCLEOSIDES

Detail account of the synthesis of 3'-azido nucleosides utilizing 3-az ido-2,3-dideoxy-D-ribose derivative 7 as the key intermediate was desc ribed. The key intermediate 7 was synthesized from D-mannitol in 8 ste ps in a preparative scale. The Michael reaction of the azide group wit h alpha,beta-unsaturated-gamma-butyrolactone 4 was affected by the ste ric bulkiness of the substituent at the 5-0 position. A bulky t-butyld iphenylsilyl substitution at 5-0 gave almost exclusively the alpha-azi do adduct 5b, while unsubstitution at 5-0 produced 1:1 mixture of alph a-and beta-adducts. The ratio of alpha to beta anomers in the condensa tion between azido acetate 7a and pyrimidine bases for the preparation of AZT and AZDU was greatly influenced by the solvent and the Lewis a cid catalyst used. In the synthesis of 12 (AZDU, CS-87), the combinati on of dichloroethane and trimethylsilyl triflate gave an optimal resul t, while in the case of 14 (AZT), various conditions gave similar rati o of alpha,beta anomers. The azido intermediate 7b was also utilized f or the synthesis of several 3'-azido purine-like nucleosides 16-27. Th e glycosylation was also affected by the Lewis acid catalyst. Boron tr ifluoride etherate gave the desired N-1-glycosylated compounds in whic h the alpha-anomer was major, but other catalysts such as trimethylsil yl triflate or stannic chloride produced N-2-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.