Note

A ¹H- and ¹³C-n.m.r. spectroscopic analysis of six pseudohexoses☆

This review describes the results of synthetic studies undertaken by the authors of this chapter on carbasugars over the last 30 years or so. These studies took advantage of the long-anticipated discovery of a sole crystalline cycloaddition adduct, which under favorable conditions could play a reliable role in laying down the foundation stone for the synthetic carbasugar chemistry. Although glycosidase inhibitors with chaperone activity have recently been evaluated as if they were a final goal, it seems from another synthetic point of view that the results accumulated have made total synthesis of natural carbaoligosaccharide validamycins and acarbose possible.

A series of carbasugars were prepared and their conformational properties studied by means of NMR spectroscopy. The results were compared to those previously found for O-, S-, and C-β-glycoside analogs. While the rotational populations of the hydroxymethyl group in O-, S-, and C-glycosides are known to depend on the structural nature of their aglycon, in carbasugars it proved to be independent of the pseudo-aglycon. This result confirms that endocyclic oxygen is necessary for the observed relationship between the structure of the aglycon and the rotational populations of the hydroxymethyl group, and indicates that the stereoelectronic exo-anomeric effect is mainly responsible for such conformational dependence.

The conformational and hydration properties of the two disaccharides methyl β-cellobioside and methyl β-laminarabioside were investigated by NMR spectroscopy and explicit solvation molecular dynamics simulations using the carbohydrate solution force field (CSFF). Adiabatic maps produced with this force field displayed 4 minima A: (Φ = 300°, Ψ = 280°), B: (Φ = 280°, Ψ = 210°), C: (Φ = 260°, Ψ = 60°), and D: (Φ = 60°, Ψ = 260°) for methyl β-cellobioside and 3 minima A: (Φ = 290°, Ψ = 130°), B: (Φ = 270°, Ψ = 290°), and C: (Φ = 60°, Ψ = 120°) for methyl β-laminarabioside. Molecular dynamics simulations were initiated from all minima. For each disaccharide, the simulation started from the A minimum was conducted for 50 ns, while the other minima were explored for 10 ns. The simulations revealed two stable minima for both compounds. For methyl β-cellobioside, the simulation minima in aqueous solution were shifted from their adiabatic map counterparts, while the simulation minima for methyl β-laminarabioside coincided with the corresponding adiabatic map minima. To validate the simulation results, NMR-derived NOEs and coupling constants across the glycoside linkage, ³J_HC and ³J_CH, were compared with values calculated from the MD trajectories. For each disaccharide, the best agreement was obtained for the simulations started at the A minimum. For both compounds, inter-ring water bridges in combination with the direct hydrogen bonds between the same groups were found to be determining factors for the overall solution structure of the disaccharides which differed from solid-state structures. Comparison with helical parameters showed that the preferred glycosidic dihedral configurations in the methyl β-cellobioside simulation were not highly compatible with the structure of cellulose, but that curdlan helix structures agreed relatively well with the methyl β-laminarabioside simulation. Polymers generated using glycosidic dihedral angles from the simulations revealed secondary structure motifs that that may help to elucidate polymer associations and small-molecule binding.

The present article reports long timescale (200 ns) simulations of four β-d-hexopyranoses (β-d-glucose, β-d-mannose, β-d-galactose and β-d-talose) using explicit-solvent (water) molecular dynamics and vacuum stochastic dynamics simulations together with the gromos 45A4 force field. Free-energy and solvation free-energy differences between the four compounds are also calculated using thermodynamic integration. Along with previous experimental findings, the present results suggest that the formation of intramolecular hydrogen-bonds in water is an ‘opportunistic’ consequence of the close proximity of hydrogen-bonding groups, rather than a major conformational driving force promoting this proximity. In particular, the conformational preferences of the hydroxymethyl group in aqueous environment appear to be dominated by 1,3-syn-diaxial repulsion, with gauche and solvation effects being secondary, and intramolecular hydrogen-bonding essentially negligible. The rotational dynamics of the exocyclic hydroxyl groups, which cannot be probed experimentally, is found to be rapid (10–100 ps timescale) and correlated (flip-flop hydrogen-bonds interconverting preferentially through an asynchronous disrotatory pathway). Structured solvent environments are observed between the ring and lactol oxygen atoms, as well as between the 4-OH and hydroxymethyl groups. The calculated stability differences between the four compounds are dominated by intramolecular effects, while the corresponding differences in solvation free energies are small. An inversion of the stereochemistry at either C₂ or C₄ from equatorial to axial is associated with a raise in free energy. Finally, the particularly low hydrophilicity of β-d-talose appears to be caused by the formation of a high-occurrence hydrogen-bonded bridge between the 1,3-syn-diaxial 2-OH and 4-OH groups. Overall, good agreement is found with available experimental and theoretical data on the structural, dynamical, solvation and energetic properties of these compounds. However, this detailed comparison also reveals some discrepancies, suggesting the need (and providing a solid basis) for further refinement.

NMR spectroscopic data for 12 pseudo-disaccharides of the general structure: (α or β)-d-glucopyranosyl-(1 → x)-5a-carba-(d or l)-glucopyranose, representing analogues of laminaribiose (β-d-Glcp, x = 3), cellobiose (β-d-Glcp, x = 4), and maltose (α-d-Glcp, x = 4) are presented. The assigned NMR chemical shifts together with NOE difference measurements in association with calculations applying the HSEA force field combined with Monte Carlo simulations have been used to assess the conformational preferences of the investigated compounds. The results are correlated with general structural features involved in the interactions between monosaccharide units of oligosaccharides.

N.m.r. data (¹H and ¹³C) are presented for eight pseudo-trehalose derivatives in which the d-glucopyranosyl moiety is α or β and the 5a-carbaglucopyranoside moiety is α-d, β-d, α-l, or β-l. The differences in the chemical shifts and the n.O.e. effects have been correlated with the preferred conformations estimated from empirical force-field calculations (HSEA), which have been used to calculate the average parameters over the whole energy surface. Of the four α-d-glucopyranosyl derivatives, only that with a 5a-carba-β-d-glucopyranoside moiety (3) was a substrate for glucoamylase.