How do the gauche and anomeric effects drive the pseudorotational equilibrium of the pentofuranose moiety of nucleosides?

Abstract

The conformational characteristics of abasic 1-deoxy sugars 1,2, and 3 and pentofuranose moieties in 2',3'- dideoxy-(ddA (6), ddG (7), ddC (S)), 2'-deoxy-(dA (9), dG (lo), dC (ll)), and ribo-@-D-nucleosides (Ade (12), Gua (13), Cyt (14)) were established through the analysis of vicinal proton-proton coupling constants extracted from their 500-MHz lH-NMR spectra recorded at 20 K intervals in the temperature range from 278 to 358 K in D20 solution. Two novel deuterated analogues of (S)-tetrahydrofurfuryl alcohol (l), 2-(S)-(hydroxymethyl)-4-(R)-deuteriotetrahy- drofuran (4) and 2-(S)-(hydroxymethyl)-3-(S)-deuteriotetrahydrofuran (5), have enabled unequivocal assignment of the complex nine-spin system in its 'H-NMR spectrum. The van't Hoff plots of (In(&/&)) as a function of 1 / Tgave AH' and AS' values of pseudorotational equilibrium in pentofuranoses 1-3 and pentofuranose moieties in nucleosides 614. The values of AH' were dissected into various stereoelectronic effects (gauche versus anomeric effects) of exocyclic substituents on the pentofuranose moiety. Clearly, the gauche effect of the 04'-C4'-C3'-03' fragment drives the pseudorotational equilibrium to the S-type conformations, while the gauche effect of the 04'-Cl'-C2'-02' fragment pushes the pseudorotational equilibrium to the N. These gauche effects are the strongest factors responsible for driving the N e S pseudorotational equilibrium. The strength of the gauche effect of the 04'-C4'-C3'-03' fragment in abasic sugars 1-3 is further tuned by the presence of a heterocyclic base at C1' in nucleosides 6-14. The relatively weaker anomeric effect of the heterocyclic base drives the N e S equilibrium to the N. The assessment of the relative strengths of the anomeric effects in 2',3'-dideoxy, 2'-deoxy-, and ribo-@-D-nucleosides has shown that the anomeric effect of the cytosine base is stronger than the anomeric effect of the adenine or guanine base. The experimental data suggest that the anomeric effect is considerably reduced as 04' experiences the electron-withdrawing effect(s) of 2'(3')-hydroxyls. The differences in the conformational preferences found in purine and pyrimidine ribonucleosides were additionally attributed to the distinct relative strength of the gauche effect of the N-C1'-C2'-02' fragment. The preference for the gauche orientation of the N-C1'-C2'-02' fragment and therefore S-type sugar conformation is affected by the nature of the purine or pyrimidine glycosyl nitrogen atom.