Conformational studies on some Cl'-branched beta-D-nucleosides by 1H-NMR spectroscopy and molecular mechanics calculations.

Solution structures of 1-(beta-D-psicofuranosyl)thymine (HMT) (5) and 1-(1'-cyano-beta-D-ribofuranosyl)-thymine (CNT) (6) based on 3JH,H coupling constants (1H-NMR at 500 MHz) and nOe enhancement studies were further refined by molecular mechanics calculations using the AMBER force field. These complementary NMR-molecular mechanics studies helped us to define the torsion angles inside the NMR-defined conformational hyperspace. Atom-centered monopole charges were derived for molecular mechanics calculations by fitting the molecular electrostatic potential on freely optimized geometries of 5 and 6 using HF/3-21G level of theory by GAUSSIAN 92 program. The conformation of 5 and 6 can be summarized as follows: (i) the pseudorotational analyses showed that the North conformer is predominant in both 5 (> 70%) and 6 (97%). While the molecular mechanics could correctly predict the energetic preference of North over South type puckered sugar moiety for 5 and 6 it could not provide any clue to the fact that the 1'-CN group in CNT (6) drives the pseudorotational equilibrium more effectively towards North than 1'-CH2OH in HMT (5). (ii). The NMR-observed preference of anti over syn conformation across the glycosyl bond in 5 and 6 was correctly shown by the energetic preference of anti conformers by approx. 10 kJ/mol. (iii) The populations of the staggered rotamers across C4'-C5' (gamma +, gamma t and gamma -) calculated from 3J4'5' and 3J4'5" coupling constants from NMR spectroscopy show that gamma + and gamma t rotamers are preferred. Molecular mechanics calculations are also in an excellent agreement here with the results of solution studies: in 5 gamma + and gamma t rotamers are equally populated and a small energy difference in potential energy is established, while in 6 the larger energy difference in potential energy is found which reflects a higher preference for gamma + rotamer in solution. The energetic preferences found among the lowest energy conformers of 5 (North-gamma +/gamma t-anti-epsilon t1) and 6 (North-gamma +/gamma t-anti) in molecular mechanics calculations are in an excellent agreement with the preferences of the major conformers found by NMR spectroscopy in solution.