Synthesis and Utility of 2‐Halo‐O⁶‐(benzotriazol‐1‐yl)‐Functionalized Purine Nucleosides

Abstract

An efficient synthesis of 2‐halo‐O6‐(benzotriazol‐1‐yl)‐substituted purine nucleosides has been accomplished via (benzotriazol‐1‐yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP)‐mediated coupling and subsequent halogenation via diazotization of the 2‐amino group of various protected guanosines and directly from guanosine itself. These products are amenable to substitution and coupling reactions in the 2‐ and 6‐positions and, accordingly, provide efficient access to highly functionalized purine nucleosides.

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

“…Considering only the nucleoside modification literature, our BOP-mediated amide-activation methodology has found wide application [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Of specific interest to our current work was a report wherein some of our results on guanosine derivatives were reevaluated [ 44 ]. In addition to 2′,3′,5′-tri- O -( t -butyldimethylsilyl)guanosine, which we had originally investigated, five other compounds were also studied: unprotected 2′-deoxyguanosine, its 2′,3′,5′-triacetyl and the 2′,3′-isopropylidene derivatives, and two 2′,3′-isopropylidiene 5′-carboxamides [ 44 ].…”

“…Of specific interest to our current work was a report wherein some of our results on guanosine derivatives were reevaluated [ 44 ]. In addition to 2′,3′,5′-tri- O -( t -butyldimethylsilyl)guanosine, which we had originally investigated, five other compounds were also studied: unprotected 2′-deoxyguanosine, its 2′,3′,5′-triacetyl and the 2′,3′-isopropylidene derivatives, and two 2′,3′-isopropylidiene 5′-carboxamides [ 44 ]. These products were subsequently tested in diazotization-halogenation reactions, en route to 2-chloro and 2-iodo adenosine analogues [ 44 ].…”

“…In addition to 2′,3′,5′-tri- O -( t -butyldimethylsilyl)guanosine, which we had originally investigated, five other compounds were also studied: unprotected 2′-deoxyguanosine, its 2′,3′,5′-triacetyl and the 2′,3′-isopropylidene derivatives, and two 2′,3′-isopropylidiene 5′-carboxamides [ 44 ]. These products were subsequently tested in diazotization-halogenation reactions, en route to 2-chloro and 2-iodo adenosine analogues [ 44 ]. 2,6-Dihalopurine ribonucleosides are more readily accessible for this purpose, as compared to 2′-deoxy derivatives.…”

“…We opted for diazotization-chlorination conditions using t -BuONO/TMSCl, a reagent combination initially introduced for nucleoside modification in 2003 [ 46 ]. We [ 47 ] and others [ 44 ] have previously used non-aqueous conditions for halogenation at the C2 position of purine nucleoside derivatives. Under these conditions, reactions of substrate 3a proceeded modestly.…”

Proton NMR investigations on 6-alkylamino-2-alkylthioadenosine derivatives

“…). So the synthesis and characterization of the modified purine nucleosides have attracted the attention of our and other many scientific teams …”