8-Aza-3-deazaguanine modification strengthens the anomeric effect and affects other conformational preferences of modified guanine nucleosides

A variable temperature-dependent H NMR conformational analysis of JHH coupling constants and NOE enhancements of a series of 8-aza-3-deaza modified guanine nucleosides 2 and 4–8 has been performed in DMSO-d6 and the results compared to those for natural nucleosides dG (1) and G (3). 8-Aza-3-deaza nucleobase modification leads to the stabilization of N-type conformers by ∆∆H of 3.1 kJ mol , which has been attributed to the strengthening of the O4 –C1 –N9 anomeric effect. The strengthening of the anomeric effect of 8-aza-3deazaguanine compared to guanine is explained by the redistribution of electron density from N9 into the pyridine moiety which facilitates nO4 → σ*C1 –N9 orbital interactions. The anomeric effect of 8-aza-3-deazaguanine in 8a3d-dG (2) is approximately 19.5 kJ mol 1 with the assumption that the steric effects of nucleobases in dG (1) and 8a3d-dG (2) are comparable. 2 and 3 -Substituents drive the N S equilibrium via their involvement in gauche effects, which are only moderately affected by the nucleobase modification. The 2 -OH group in ribo (4), xylo (7) and 3 -deoxyribo (8) counterparts, however, drives the N S equilibrium towards S by the gauche effect of the [N9–C1 –C2 –O2 ] fragment, which has been strengthened by ∆∆H of 1.8 kJ mol 1 due to 8-aza-3-deaza nucleobase modification. 2 -F in the arabino analogue 8a3d-FaraG (6) showed conformational preferences which are nucleobase specific and could not be attributed to the gauche effects. The larger population of γ rotamers in 1–8 correlates with the larger population of N-type conformers.