A Computational Study of Methyl α-D-Arabinofuranoside:  Effect of Ring Conformation on Structural Parameters and Energy Profile

Abstract

Ab initio molecular orbital calculations at the HF/6-31G* level of theory and density functional theory calculations at the B3LYP/6-31G* level have been carried out on methyl R-D-arabinofuranoside (1). All 10 possible envelope forms were constructed and minimized, providing a partial energy surface which identified 3 E as the lowest energy north conformer and, depending on the level of theory used, either 2 E or E 1 as the southern hemisphere minimum. The southern conformation was the global minimum regardless of the level of theory. The energy profile identifies pseudorotation through the eastern pathway as the most favorable. Pseudorotation through the west is higher in energy and similar to inversion through the planar species. The dependence of structural parameters (i.e., bond distances, bond angles, dihedral angles, and interatomic distances) on the ring conformation have been determined. Energy profiles based on additional electron correlation and extended basis sets with the HF/6-31G* geometries are presented and provide qualitatively similar results to the B3LYP/6-31G* profile.

Approach for the Simulation and Modeling of Flexible Rings: Application to the α-d-Arabinofuranoside Ring, a Key Constituent of Polysaccharides from Mycobacterium tuberculosis

“…Figure 6 contains the variation in P, which describes ring puckering; the inset shows the variation in puckering amplitude, ϕ m . The distribution in ϕ m is centered about 35°, which corresponds well to earlier ab initio, density functional theory, and molecular calculations [15][16][17][18][19] on 1 as well as to the puckering amplitude of this molecule in the crystal structure. 43 With regard to P, conformations with values in the northern hemisphere of the pseudorotational itinerary (Figure 2) are clearly favored although a small fraction of the conformers are also present in the southern hemisphere.…”

“…However, while there is good agreement with the identify of the N conformer, the conformer populations obtained from the simulation do not correspond well with experiment nor with previous ab initio and density functional theory calculations on 1. [15][16][17][18][19] Indeed, the distribution shown in Figure 7 suggests that a while a small population of the S conformer (centered around P = 180) is present, the equilibrium is heavily biased to the N conformer. These results suggest that the two-state model inherent in the PSEUROT approach may not be valid for 1.…”

“…These differences may arise from the fact that in the ab initio study a full sampling of conformational space was not undertaken. Instead the energy-minimized structures were obtained by full optimization of a family of 30 ring-constrained conformers 15 that had been partially optimized to probe the effect of ring conformation on various molecular parameters, e.g., bond lengths and bond angles. In solution, this strong correlation between the C4-C5 rotamer and the furanose ring conformation is not observed.…”

“…Although intriguing, there are scant data to support the flexible scaffold hypothesis. As part of a program dedicated to understanding the conformation of mycobacterial AG (and LAM), we have carried out a series of NMR studies on the arabinofuranose-containing oligosaccharides 13,14 and coupled these experimental studies with high-level ab initio and density functional theory calculations on methyl α-D-arabinofuranoside (1, Figure 1) 15,16 and related analogs. [17][18][19][20] Given their inherent flexibility, the conformational analysis of furanosides is more complicated than comparable studies with pyranosides as more than one ring conformer must be considered.…”

d-ARABINOFURANOSIDES FROM MYCOBACTERIA: SYNTHESIS AND CONFORMATION

“…[116] A protocol developed by Serianni and coworkers, [117,118] was used to construct the 10 possible envelope forms by fixing four atoms in a plane; then, upon minimization, the other parameters (bond lengths, bond angles, etc.) were optimized.…”