North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity

✍ Scribed by Pamela L. Russ; Maria J. Gonzalez-Moa; B. Christie Vu; Dina M. Sigano; James A. Kelley; Christopher C. Lai; Jeffrey R. Deschamps; Stephen H. Hughes; Victor E. Marquez

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 363 KB
• Volume: 4
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200900153

✦ Synopsis

Abstract

The syntheses of new conformationally locked North‐ and South‐bicyclo[3.1.0]hexene nucleosides is reported. The North analogues were synthesized by a convergent approach from the known (1__S,2__R__,5__R__)‐5‐[(tert‐butyldiphenylsilyloxy)methyl]bicyclo[3.1.0]hex‐3‐en‐2‐ol by Mitsunobu coupling with the nucleobases. The South analogues were synthesized from their bicyclo[3.1.0]hexane nucleoside precursors by the selective protection of the primary hydroxy group, conversion of the secondary alcohol into a good leaving group, and base‐catalyzed elimination to generate the olefin. The transformation of a bicyclo[3.1.0]hexane nucleoside into a bicyclo[3.1.0]hexene nucleoside flattens the five‐membered ring of the bicyclic system and rescues anti‐HIV activity for North‐D4T, North‐D4A, and South‐D4C. The relationship between planarity and the__ anti__/__syn disposition of the nucleobase that is favored by a particular pseudosugar platform are proposed as key parameters in controlling biological activity.