Nucleophilic substitution at the 4'-position of nucleosides: new access to a promising anti-HIV agent 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine.
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-glycero-pent-4-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 Me3SiCCAl(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.
Haraguchi
Kazuhiro
K
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. harakazu@pharm.showa-u.ac.jp
Sumino
Masanori
M
Tanaka
Hiromichi
H
D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D009705:Nucleosides / Q000737:chemistry*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D019380:Anti-HIV Agents; D007202:Indicators and Reagents; D009705:Nucleosides; C486840:2',3'-didehydro-3'-deoxy-4'-ethynylthymidine; D018119:Stavudine; D013936:Thymidine