Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Synthesis of 4'-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4'-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-alpha-L-threo-pentofuranosyl]thymine (8 alpha) and the 4'-(benzenesulfonyl)thymidine derivative (8 beta). The reaction of 8 alpha with organosilicon reagents (Me3SiCH2CH=CH2 and Me3SiN3) in combination with SnCl4 gave preferentially the 4'-substituted beta-D-isomer: the 4'-allyl (12 beta) and 4'-azido (15 beta) derivatives, respectively. The reaction of 8 alpha with AlMe3, however, gave the 4'-methyl-alpha-L-isomer (16 alpha) as the major product, presumably through an ion pair mechanism. By employing the substrate 8 beta in this reaction, the 4'-methylthymidine derivative (16 beta) was obtained exclusively in high yield. The 4'-ethyl (20 beta) and 4'-cyano (24 beta) derivatives were also synthesized by reacting 8 beta with the respective organoaluminum reagent. (C) 2009 Elsevier Ltd. All rights reserved.