The tunable transmission of the aromatic character of the aglycone through the anomeric effect in C-nucleosides drives its own sugar conformation: A thermodynamic study

Abstract

Abstract The anomeric and the gauche effects are two competing stereoelectronic forces that drive the North (N) (C2′-exo-C3′-endo) ⇆ South (S) (C2′-endo-C3′-exo) pseudorotational equilibrium in nucleosides (ref 1). The quantitation of the energetics of pD dependent N ⇆ S pseudorotational equilibria of the pentofuranose moiety in C-nucleosides 1 – 7 shows that the strength of the anomeric effect of the constituent heterocyclic moiety at C1′ is dependent upon the unique aromatic nature of the nucleobase, which is tuned by the pD of the medium. The force that drives the protonation ⇆ deprotonation equilibrium of the heterocyclic nucleobases in C-nucleosides is transmitted through the anomeric effect to drive the two-state N ⇆ S pseudorotational equilibrium of the constituent furanose (the energy pump), which is supported by the following observations: (i) The enhanced strength (ΔΔG 298 (P-N) of the anomeric effect in the protonated (P) nucleoside compared to the neutral (N) form is experimentally evidenced by the increased preference of N-type sugar conformation with pseudoaxial nucleobase by 2.0 kJ/mol for formycin B ( 1 ), 1.4 kJ/mol for formycin A ( 2 ), 1.4 kJ/mol for 9-deazaadenosine ( 3 ) and 1.9 kJ/mol for Ψ-isocytidine ( 4 ). (ii) In contrast, the S-type sugar conformer, which places the nucleobase in pseudoequatorial orientation, is considerably more preferred in the alkaline medium owing to the weakening of the anomeric effect in the N1 deprotonated (D) formycin B, and N3-deprotonated Ψ-isocytidine, Ψ-uridine and 1-methyl-Ψ-uridine compared to the neutral counterparts by ΔΔG o (N-D) of 0.2 kJ/mol for formycin B ( 1 ), 1.6 kJ/mol for Ψ-isocytidine ( 4 ), 1.7 kJ/mol for Ψ-uridine ( 5 ), 0.8 kJ/mol for 1-methyl-Ψ-uridine ( 6 ). (iii) The quantitation of the pD-dependent drive of N ⇆ S pseudorotational equilibria in C-nucleosides 1 – 6 has allowed us to independently measure the pK a of the constituent heterocyclic nucleobases. (iv) A simple comparison of ΔG N 298 or ΔG P 298 or ΔG D 298 values of all C-nucleosides 1 – 7 (Table 1) with N-nucleosides (ref 1) shows that the C1′ substituent promoted anomeric drive of N ⇆ S equilibrium to N-sugar is weaker in C-nucleosides than in N-nucleosides, but their respective flexibilities from the neutral to the protonated or to the deprotonated state is completely aglycone-dependent.