Quantitation of the Anomeric Effect in Adenosine and Guanosine by Comparison of the Thermodynamics of the Pseudorotational Equilibrium of the Pentofuranose Moiety in N- and C-Nucleosides

Abstract

The effect of N-aglycones at C1’ on the drive of two-state north (N (C3’-endo-C2’-exo)) * south ( S (C2’endo-C3’-exo)) pseudorotational equilibrium in 8-D-ribofuranosyl-N-nucleosides consists of two counteracting contributions from (i) the anomeric effect (stereoelectronic interactions between furanose 04’ and the nucleobase nitrogen at Cl’), which places the aglycone in the pseudoaxial orientation, and (ii) the inherent steric effect of the nucleobase, which opposes the anomeric effect by its tendency to take up pseudoequatorial orientation. The maximum pseudoequatorial orientation of the nucleobase is sterically possible only in the S-type conformations. Therefore, the extent of this pseudoequatorial orientation can be experimentally determined by the extent of the thermodynamic stabilization of the S conformer in the two-state N + S equilibrium (ref 1 ) . This means that a direct measurement of the extent of thermodynamic stabilization of the S conformer amongst a set of various 8-D-ribofuranosyl-C-nucleosides, where the absence of the anomeric effect has been previously established from X-ray studies (ref 6 ) , should give us a reference point for the maximally pseudoequatorially oriented C-nucleobase. We report here the characterization of this reference 8-D-ribofuranosyl-C-nucleoside. The subtraction of the AP of its pseudorotational equilibrium from the AP of P-D-ribofuranosyl-N-nucleosides gave the quantitative insight of the anomeric effect in adenosine (+9.1 kJ/mol) and guanosine (+10.5 kJ/mol) for the first time. We have found that the C-aglycones in formycin A (1 ) and B (2) constitute the optimal reference point (ref 12) for our purpose because they take up the predominantly favored pseudoequatorial orientation (closer to the limit), where the steric control is almost the exclusive determinant, owing to the negligible presence of any stereoelectronic interaction with the lone pairs of furanose-04’ (see Table 3 ) .