Highly efficient synthesis of 2,2′-anhydro-1-(3′-bromo-3′-deoxy-5′-O-trityl-β-D-arabinofuranosyl)thymine and its derivatives from an unsaturated thymine nucleoside

Abstract

Reaction of 5′-O-trityl-2′,3′-thymidinene 1 with hypobromous acid gave (5R,6R)-2,2′-anhydro-5-bromo-1-(3′-bromo-3′-deoxy-5′-O-trityl-β-D-arabinofuranosyl)-6-hydroxy-5, 6-dihydrothymine 3a and its (5S,6S)-trans isomer 4a. Similarly, 6-methoxy analogues (3b and 4b) and 6-acetoxy analogues (3c and 4c) of 3a and 4a were synthesized. Compounds 3a and 4a were converted into the corresponding 5,6-epoxy derivatives, 5 and 6. Deoxygenation of oxiranes 5 and 6 with Ph3P gave 2,2′-anhydro-1-(3′-bromo-3′-deoxy-5′-O-trityl-β-D-arabinofuranosyl)thymine 7, which was also obtainable in excellent yields from compounds 3a, b or/and 4a, b by treatment with Ph3PNaHCO3, or directly from unsaturated furanose 1 by one-pot synthesis via methyl ethers 3b and 4b or acetates 3c and 4c. Compound 7 was deprotected to give the mother compound 8 and was also converted into the 2, 3-lyxo epoxy thymine furanosides, 11 and 12, in high yields.