Nucleophilic substitution at the 4 '-position of nucleosides: New access to a promising anti-HIV agent 2 ',3 '-didehydro-3 '-deoxy-4 '-ethynylthymidine

摘要

For the synthesis of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (8: 4'-Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-beta-L-glyceropent4- enofuranosyl) thymine with Pb(OBz) 4 allowed the introduction of the 4'-benzoyloxy leaving group, nucleophilic substitution at the 4'-position became feasible for the first time. Thus, reaction between the 4'-benzoyloxy derivative (14) and Me3SiC CAl(Et) Cl as a nucleophile led to the isolation of the desired 4'-"down"-ethynyl derivative (18) stereoselectively in 62% yield. As an application of this approach, other 4'-substituted nucleosides, such as the 4'-allyl (24a) and 4'-cyano (26a) derivatives, were synthesized using organosilicon reagents. In these instances, pretreatment of 14 with MeAlCl2 was necessary.