Stereochemical studies on nucleic acid analogues. I. Conformations of α -nucleosides and α -nucleotides: interconversion of sugar puckers via O4'-exo

Abstract

The preferred conformations of ribo and deoxyribo α -nucleosides andβ -nucleotides, the stereoisomers of the naturally occurring β -isomers, are worked out by minimizing the conformational energy as a function of all the major parameters including the sugar ring conformations along the pseudorotation path. The results of the studies bring out certain distinct conformational features that are at variance with their β counterparts. The range of glycosyl conformations are found to be not only quite restricted here but favor predominantly the anti conformation. The syn glycosyl conformation for the entire region of α values are found to be energetically less favorable, with the barrier to anti ⇆ syn interconversion being higher especially inα -ribonucleosides. The energetically preferred range of pseudorotation phase angles (P) is also considerably restricted and P values corresponding to the C1'-exo range of sugars are highly unfavorable for α -nucleosides, in sharp contrast to the broad range of sugar ring conformations favored by β -isomers. While both trans ≅ 180° and skew ≅ 270° conformations around the C3'-O3' (φ ') bond are favored for β -3'-nucleotides with deoxyribose sugars, ribose sugars seem to favor only the skew values of φ'. Most interestingly and in sharp contrast to β -stereoisomers, an energy barrier is encountered at P values corresponding to O4'-endo sugars. This suggests that the possible sugar pucker interconversion between C2'-endo/C3'-exo and C3'-endo/C2'-exo in a-anomers could take place only through the O4'-exo region. Likewise the possible path of anti ⇌ syn interconversion in α-nucleosides is not via high anti, in sharp contrast to α-nucleosides. These observations should be borne in mind while assigning the sugar ring conformers in α -nucleosides and those containing them from nmr investigations. Comparison of the results with α -anomers seem to suggest on the whole a lack of conformational variability or the restricted nature of α -stereoisomers. This could be one of the reasons for its nonselection in the naturally occurring nucleic acids.