Generalized anomeric effect

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

In summary, for O-glycosides, a-anomers (a-D and oc-l) are thermodynamically more stable than the p-anomers (p-D and p-L) due to the anomeric effect. Therefore l,2-c -a-D- or a-L-glycosides are preferentially obtained, in general. On the other hand, the lower stability of glycosides such as p-D-arabinosides and p-D-mannosides requires special methods for their preparation, thus promoting the development of new synthetic methodologies. 

An NMR study on the conformation of glucopyranosylammonium compounds showed that the general tendendency of many electronegative substituents at C(i) to adopt an axial conformation was prevalent in this case too, as depicted in equilibrium 36 for R groups of various sizes. These results disclaim the importance of the so-called reverse anomeric effect 404. 

The conformational energies of monosubstituted oxanes studied to date are collected in Table I. In position 2, polar substituents (except NR2) prefer the axial position other substituents prefer the equatorial orientation, which is generally the case for groups in positions 3 and 4. Destabilizing 1,3-diaxial interactions cause the equatorial geometry to be usually favored in the 2-position, the anomeric effect stabilizes the axial conformation. A large purine moiety in position 2 of oxane, for example, prefers the equatorial position because the 1,3-diaxial interactions overcome the anomeric effect (75TL1553). 

By definition, a generalized anomeric effect is observed at carbon of an XCY system when a molecule preferentially adopts a conformation that optimizes a secondary, stabilizing electronic interaction involving overlap between the lone pair on one heteroatom with the a orbital of the bond between the central carbon atom and the second heteroatom . Figure 5a illustrates that in XNY systems, as with anomeric carbon centres, two anomeric interactions are possible and involve either an ny-CT x ° nx-o NY overlap where nx and ny represent the p-type lone pairs on X and Y and NX and NY represent the N—X and N—Y a orbitals. In either case, the result is a net stabilization of the lone pair of electrons (Figure 5b). Except where the nitrogen is symmetrically substituted, one of these interactions will be strongest. 

A parameter that has been useful for defining the anomeric stereochemistry of glycopyranosides is the chemical shift of the anomeric carbon atom, C-l. Similarly, the 13C NMR shifts of C-l in methyl septanosides also diagnostic for their anomeric configuration. In general, the Sc.i values for a-septanosides are slightly upfield (99-104 ppm in completely deprotected septanosides) relative to (S-septanosides (104-111 ppm) (Table I). This distribution of chemical shifts mirrors the trends for pyranosides namely, the C-l chemical shifts for a-pyranosides lie upfield from those of p-pyranosides. This observation suggests that the anomeric effect is operative in... 

In the conformational equilibrium (Fig. 22) for 5-methyldihydro-l,3,5,-dioxazine (454) the generalized anomeric effect favors the N-Meax conformer 455 and, in addition (relative to jV-Meax piperidine), 455 does not contain the two unfavorable syn-axial interactions involving the axial N-methyl... 

The successive change in position of the N-Mem N-Meeq equilibrium from that in 5-methyldihydro-l,3,5-dioxazine (AG° > 1 kcal mol-1) to 3-methyltetrahydro-l,3-oxazine (AG° 0.10 + 0.05 at — 120°C) to that (AG° —2.7 kcal mol-1) in 1-methylpiperidine results from successive differences of syn-axial interactions involving the axial methyl group and a favoring of the axial methyl conformer by the generalized anomeric effect. 

A general conclusion from the data on the halides is that the anomeric effect strongly outweighs conventional steric factors in determining conformational behavior. 

Fig. 4. Modelling of the torsion potential of the exo anomeric effect using the results of the ab initio calculation of dimethoxymethane. The difference between the non bonded terms and the ab initio calculation is fitted with the general function of torsion potentials to yield the equations for the oc-and the P-anomers discussed in Sect. 2.5.3 for the HSEA method...

---