An Alternative Synthetic Method for 4′-C-Ethynylstavudine by Means of Nucleophilic Substitution of 4′-Benzoyloxythymine Nucleoside

Abstract

For the synthesis of 2′,3′ -didehydro-3′ -deoxy-4′ -C-ethynylthymidine (8: 4′ -Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-β-l-glycero-pent-4-enofuranosyl)thymine with Pb(OBz)₄ allowed the introduction of a 4′-benzoyloxy leaving group, nucleophilic substitution at the 4′ -position became feasible for the first time. Thus, reaction between the 4′-benzoyloxy derivative (11) and Me₃SiC ≡ CAl(Et)Cl as a nucleophile led to the isolation of the desired 4′-“down”-ethynyl derivative (15) stereoselectively in 62% yield.

Keywords:

• Anti-HIV
• diacyloxylation
• 4′,5′-unsaturated nucleoside
• nucleophilic substitution
• ethynylation
• 4′-substituted nucleosides
• didehydro-3′-deoxythymidine
• organoaluminum reagents
• organosilicon reagents

Acknowledgments

Financial support from the Japan Society for the Promotion of Science (KAKENHI No. 17590093 to K. H. and No. 17590094 to H. T.), the Research Foundation of Pharmaceutical Sciences (to K. H.), and the Japan Health Sciences Foundation (SA14804 to H. T.) are gratefully acknowledged.