Conformational studies on some C1′-branched β- d-nucleosides by 1H-NMR spectroscopy and molecular mechanics calculations

Abstract

Solution structures of 1-(β- d-psifuranosyl)thymine (HMT) ( 5) and 1-(1′-cyano-β- d-ribofuranosyl)-thymine (CNT) ( 6) based on 3 J H,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 mechanis 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′-CH 2OH 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 acrosss C4′-C5′( γ +, γ t and γ −) calculated from 3J 4′5′ and 3J 4′5′ coupling constants from NMR spectroscopy show that γ + and γ t rotamers are preferred. Molecular mechanics calculations are also in an excellent agreement here with the results of solution studies: in 5 γ + and γ 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 γ + rotamer in solution. The energetic preferences found among the lowest energy conformers of 5( North-γ +/γ t -anti-ϵ 1 t and 6 (North- γ +/ γ t- anti in molecualr mechanics calculations are in an excellent agreement with the preferences of the major conformers found by NMR spectroscopy in solution.