Synthesis of (±)-4′-Ethynyl and 4′-Cyano Carbocyclic Analogues of Stavudine (d4T)

Abstract

The synthesis of (±)-4′-ethynyl (8) and 4′-cyano (9) carbocyclic analogues of the anti-HIV agent stavudine (5, d4T) is reported. The carbocyclic unit (16) was constructed from readily available β-keto ester 10. The ethynyl or cyano group of 8 and 9 were prepared, after the introduction of thymine base to 16, by manipulation of the ester function. Evaluation of the anti-HIV activity of 8 and 9 was also carried out.

This work was financially supported in part by grants from the Japan Health Sciences Foundation (SA14718 to H. T.), Japan Society for the Promotion of Science (KAKENHI No. 15790075 to H. K., No. 15590100 to K. H., and No. 15590020 to H. T.), and NIH USA (RO1 AI 38204 to Y.-C. C.).

Keywords:

• Stavudine
• 4′-ethynyl-d4T
• Carbocyclic nucleoside

Notes

This work was financially supported in part by grants from the Japan Health Sciences Foundation (SA14718 to H. T.), Japan Society for the Promotion of Science (KAKENHI No. 15790075 to H. K., No. 15590100 to K. H., and No. 15590020 to H. T.), and NIH USA (RO1 AI 38204 to Y.-C. C.).

^aFor example, see Ref. 23

^bFor the preparation of the diazophosphonate: Ref.25.

^cSynthesis of 4′-cyano-2′-deoxy purine nucleosides has recently been reported: Ref. 26.