Intramolecular hydrogen bonding and molecular conformations of nucleosides: N(6)-Dimethyl-2′,3′-isopropylidene adenosine

Abstract

The physical properties of an adenosine derivative, N(6)-dimethyl-2′,3′- O-isopropylidene adenosine, Derivative 1, which is capable of intramolecular hydrogen bond formation between base-ring and sugar exocyclic hydroxymethyl group, have been studied in solution by infrared, circular dichroic and nuclear magnetic resonance spectroscopy. Analysis of the 220 MHz 1H NMR spectrum of Derivative 1 in C 2HCl 2 solution indicated an overwhelming preference for the gg conformation for rotation about the C(4′)-C(5′) bond and a predominant conformation for rotation about the C(5′)-O(5′) bond in which OH(5′) projects towards the base ring. The purine base ring was shown to be in a predominant syn conformation with respect to the sugar ring by 100 MHz 1H nuclear Overhauser experiments, by analysis of 3J( 13 C,H1′) magnitudes observed in proton-coupled 13C NMR experiments and by CD measurements. Combination of each conformational feature of Derivative 1 in non-polar solvents is consistent with the overall molecular conformation observed in the solid state in which intramolecular hydrogenbonding exists between purine N(3) and the sugar CH 2OH group; the presence of a strong intramolecular hydrogen bond was observed by infrared spectroscopy. The sugar ring conformations of 2′,3′- O-isopropylidene ribonucleosides were analysed in terms of the pseudorotational properties of the ring; the N and S conformations tend toward to C(2′)- exo and C(3′)- exo conformations, respectively, compared to normal ribonucleosides (C(3′)- endo and C(2′)- endo, respectively). The presence of the hydrogen bond in the derivative is sufficient to promote the S-type conformations (approx. 80–90%) compared to cases where such a strong hydrogen bond is unlikely to be present (approx. 40–50%).