Synthesis of 4-Substituted 1H-Benzimidazole 2′-Deoxyribonucleosides and Utility of the 4-Nitro Compound as Universal Base

The stereoselective synthesis of 4-substituted 1H-benzimidazole 2′-deoxyribonucleosides is described. Regioisomeric (N¹ and N³) β-D -deoxyribonucleosides 2a–c and 3a–c were formed. ¹³C-NMR Chemical shifts of the 1H-benzimidazole 2′-deoxy-β-D -ribofuranosides were correlated with point charges of C-atoms as well as with Hammett constants of the exocyclic substituents. Phosphonate and phosphoramidite building blocks of 4-nitro-1H-benzimidazole 2′-deoxyribofuranoside ( 2a ) were prepared (see 4a, b ). Oligonucleotides of the d(A₂₀) type were synthesized in which the two central dA bases were replaced by 4-nitro-1H-benzimidazole residues. They were hybridized with oligomeric dT and related oligomers having the other conventional bases opposite to the 4-nitro-1H-benzimidazole moieties. Within these duplexes ( 12·13, 12·14, 12·15 , and 12·16 ), the destabilization was almost independent of the mismatch which is required for a universal base. The thermodynamic data indicate that the 4-nitro-1H-benzimidazole residues do not form H-bonds with opposite bases but are stabilizing the duplex by stacking interactions and favorable entropic changes.