How Do the Gauche and Anomeric Effects Drive the Pseudorotational Equilibrium of the Pentofuranose Moiety of Nucleosides?

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)-deuteriotetrahydrofuran (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 a t 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. The pseudorotation concept was introduced to describe the continuous interconversions of puckered forms of the cyclopentane ring.l The furanose geometry is conveniently described using the puckering parameters based on the endocyclic torsion angles.2~~ The AltonaSundaralingam parameters are the phase angle of pseudorotation (P) and a puckering amplitude (Qm); P defines the part of the ring which is most puckered, and Qm indicates the extent of p~ckering.~.~ The pseudorotation cycle, in which Pvaries from 0’ to 360’ through a set of 20 distinct twist and envelope conformations can be subdivided into North (P = O’), East (P = 90°), South (P = 1 80°), and West (P = 270’) regions (Scheme I ) . 2 9 3 A survey of 178 X-ray crystal structures of nucleosides and nucleotides found nucleosides in both North (N) and South (S) conformations (Scheme I).4 The first range is centred around P = 18’ (C3’-endo), whereas the second range is in the South part and is centred around P = 162’ (C2’-endo). However, there are a few examples of both X-ray4 and solution5 structures which havesugar conformations with P= 90”. TheseEast (E) structures support the hypothesis that the N e S interconversion proceeds through the E rather than the West (W) conformation. The values of \km were found in a range from 30’ to 46’, and most of them fall within 38.6’ f 3.0°.4 For 178 b-D-furanoside moieties, the ratio between N and S states in ribonucleosides is approximately 1: 1, and for 2’-deoxyribonucleosides, it is 1:3.4 e Abstract published in Advance ACS Abstracts, September 15, 1993. (1) Kilpatrick, J. E.; Pitzer, K. S.; Spitzer, R. J . Am. Chem. SOC. 1947, (2) Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94, 8205. (3) Altona, C.; Sundaralingam, M. J. Am. Chem. SOC. 1973, 95, 2333. (4) de Leeuw, H. P. M.; Haasnoot, C. A. G.; Altona, C. Zsr. J . Chem. 1980, (5) Hoffmann, R. A.; van Wijk, J.; Leeflang, B. R.; Kamerling, J. P.; 69, 2483.