Conformational studies anomers

The polysaccharides are, after the proteins and the nucleic acids, the third important group of biological polymers. From the point of view of the quantum-mechanical calculations of their conformational problems, mention may be made in the first place of the work of Neely 13> who has studied by the Extended Hiickel Theory the relative conformational stabilities of a few of the different possible chair and boat conformations of D-glucose, II. Within the conformations studied, the chair one, known under the designation Cl, appears so far the most stable. Experimentally, it is apparently the most stable of all. Moreover, the (3-anomer comes out as 9 kcal/mole more stable than the a-one. Although this difference is far too large with respect to experiment, it is in the proper direction. 

The syn-anti conformational problem of a- and /3-pyrazofurins (756 one of the rare naturally occurring pyrazole compounds, see Section 4.04.4.4.3), which involves a rotation around a pyrazolic sp carbon atom and a sugar sp carbon atom, has been studied theoretically using the PCILO method (81MI40403). In agreement with the experimental observations, the /3 anomer is energetically more favourable than the a anomer, the preferred conformations being anti and syn, respectively. 

The pyranoid monosaccharides provide a wide range of asymmetric molecules for study by the c.d. spectroscopist. However, these compounds are not without their difficulties. In aqueous solution, these compounds exist in a complex equilibrium involving the two possible chair conformers of the pyranoses, the furanoses, a and p anomers, and the acyclic form, as well as septanoses for aldohexoses and higher sugars. 

Alternatively, lactols react with benzenesulfinic acid in the presence of CaCl2 to yield the sulfones, again at room temperature [307,309]. In the axial series, the bulk of the sulfone group is such that the 4Cj chair is not always the preferred conformation, and it has been shown that a twist-boat conformer is adopted in at least one instance [305]. Nevertheless, equilibration studies have shown that the sulfonyl group has a small anomeric effect and that the axial anomer is preferred [310],... 

D-galactose, methyl a- and 0-D-glucopyranosides, and a number of disaccharides, thus demonstrating that mass spectrometry is useful in the field of carbohydrate chemistry. In this study, the appearance potentials of CjHnOs ions were measured, and the results interpreted in terms of greater stability of the /9-(d or l) (equatorial) anomer with respect to the o-(d or l) (axial) one in the CA conformation. 

A kinetic study of the methyl glycosidation of D-mannose was also made by Mowery.48 The more stable anomer, the a-D-mannofuranoside, was formed at a higher initial rate (see Table III) the proportions of both furanosides in the final equilibrium mixture was too small to permit accurate comparison of isomer distribution. The conformational stability of the D-mannofuranosides may be compared with that of the D-lyxo-furanosides the furanoid structures are similar, except for the bulky two-carbon group at 04 of the hexoside. This similarity is shown in the very small proportion of n-lyxofuranosides (see Table V) and of D-manno-furanosideo (see Table III) in the final equilibrium mixtures, and also in the initial formation of D-mannopyranosides48 and of D-lyxofuranosides.u... 

The MO explanation for the anomeric effect considers the n-a overlap between the lone-pair of Y and the vacant a orbital of the C—X bond. This stabilizing interaction is more effective when X is axial and thus the axial conformer is favoured. The electrostatic explanation invokes the destabilizing interaction between the dipole moment of the C—X bond and the dipole moment resulting from the C—Y bond and the lone-pairs of Y. Such dipole/dipole interactions are minimized when X is axial and again the axial conformer is preferred in the gas phase or in nonpolar solvents. It is not so easy to distinguish between the relative importance of each interaction. However, the observation that the axial preference is diminished by increasing solvent polarity is best explained by the electrostatic interaction model [82, 282-284], The unfavourable electrostatic dipole/dipole repulsion in the equatorial anomer decreases with increasing solvent polarity, and hence the equilibrium shifts towards the equatorial conformer in polar solvents. This solvent-dependent anomeric effect has been particularly well studied with 4,6-dimethyl-2-methoxytetrahydropyran [283, 284] and 2-methoxy-1,3 -dimethylhexahydropyrimidine [282]. 

In Table 7.11, we list the results of four computational studies that address the glucose anomer population in solution. All four studies use a number of conformers of each anomer and treat the solvent with either SM or PCM. As with their prediction for gas-phase populations, these four methods are generally in good agreement the MP2 results again appear to overestimate the a population. 

The agreement in the anomeric populations between experimental and computational studies is certainly encouraging. The computations correctly predict the inversion of anomeric preference between the gas and solution phases. However, there are some underlying concerns. Solution-phase NMR studies have determined the populations of the glucose conformations. The experimental populations of the gg (6a, 6f, 7a, 7b), gt (6b, 7c, 7d), and tg (6c, 7e, 7h) conformations is 51 47 2 for the a anomer and 53 45 2 for the p anomer.The computational studies of Table 7.11 predict that the gt conformations will dominate the populations for both the a and p anomers. 

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