¹H NMR conformational study of a variety of α-anomers of C5-substituted 2′-deoxyuridines: Comparison to their antiherpetic β counterparts

Although α-nucleosides are not found in nucleic acid, they do occur as constituents of smaller molecules in living cells, e.g., in vitamin B₁₂. There are now several examples of α-nucleosides exerting a biological activity in some instances equal to, or even exceeding, that of the corresponding β-anomer. Examples include growth inhibitory properties against mouse leukemia cells and antitumor activity. From stereochemical point of view, α-anomers serve as references for studying of interaction of the base with the sugar moiety in β-anomers and may help in better understanding of structure-activity relationships. One important problem preventing conformational analysis of α nucleosides is uncertainty in the determination of vicinal coupling constants from simulation of overlapping sugar proton resonances of strongly coupled spin systems. A successful resolution of near-isochronous H3′ and H4′ resonances made possible a full conformational analysis for a series of α-anomers C5-substituted 2′-deoxyuridines, including methyl, ethyl, isopropyl, fluor, vinyl, and bromovinyl, in comparison to their β counterparts. Conformation of the sugar ring is determined from proton-proton coupling constants and described in terms of pseudorotation between two main puckering domains C2′endo (S) and C3′endo (N). A thorough analysis of chemical shifts as well as conformation of the sugar ring and C4′-C5′ rotamers made possible determination of conformational preferences in equilibrium about the glycosidic bond between two regions, anti and syn. This work provides insights into the role of anomeric configuration of the base in conformational behavior of the sugar moiety, a link in the backbone of nucleic acids.