How S–C–N anomeric effects and energetic preference across [S–C–C–O] fragments steer conformational equilibria in 4′-thionucleosides. 1H NMR and ab initio MO study †

Abstract

Variable temperature- and pH-dependent 1H NMR conformational analyses of 3JHH coupling constants and NOE enhancements in the 4′-thionucleosides 1–10 in D2O, complemented by ab initio calculations, have given insight into the interplay of anomeric and other stereoelectronic effects that are modulated by the substitution of ring oxygen by sulfur in natural nucleosides. The N⇌S pseudorotational equilibrium of the 2′-deoxy-4′-thionucleosides 1–4 is slightly shifted towards S-type conformers, while their ribo analogues 5–8 exhibit ca. 50∶50 ratio at 278 K and neutral pH. α-4′-Thionucleosides 9 and 10 display a strong preference for N-type conformers. The S–C–N anomeric effect in 1–4 is stronger in purine than in pyrimidine 4′-thionucleosides, which is opposite to natural 4′-oxonucleosides, and increases in the following order: thymine < cytosine < guanine < adenine. The S–C–N anomeric effect in 1–4 is weaker than the O–C–N anomeric effect in their 4′-oxo counterparts. We have observed considerable population of up to 40% of γ− rotamers across the C4′–C5′ bond, which has been attributed to the preference of the [S4′–C4′–C5′–O5′] fragments in 1–10 for trans over gauche conformation. Similarly, the 3′-OH group drives the N⇌S equilibrium in 1–10 towards N where the [S4′–C4′–C3′–O3′] fragment adopts trans conformation. The 2′-OH group has been found to preferentially stabilise N-type sugar conformation in the 4′-thioribonucleosides 5–8 where it occupies a pseudoaxial orientation. The pKa values in 1–10 are almost identical to the pKa values of their natural counterparts, which shows that the acid–base character of the constituent heterocyclic moieties does not change upon substitution of oxygen with sulfur atom. The shift of the N⇌S pseudorotational equilibrium in 1–8 towards N upon protonation and towards S upon deprotonation of the nucleobase is smaller by up to 10 percentage points in comparison to their 4′-oxo counterparts. This can be attributed to less efficient tuning of the S–C–N anomeric effect in 1–8 by protonation and deprotonation of the nucleobase. 1D difference NOE experiments indicated predominant anti orientation of the nucleobase in 2–10. Ab initio calculations at up to MP2/6-31G**//6-31G** level have shown two energy minima in the North and South regions of conformational space with the energy barriers between 17.5 and 28.5 kJ mol−1 in the East region. Interestingly, the energy barrier in the West region is comparable or even lower than the barrier in the East region of conformational space in 1–10, which is in contrast to natural nucleosides.