Anomeric effect reversed

Since the presentation of this lecture, Wolfe, Whangbo and Mitchell [Carbohydr. Res. (1979) 69, 1] have given an excellent overview of the anomeric effects, exo-anomeric effects, reverse anomeric effects and analyzed the C-X and C-Y bond lengths in XCH2YH molecules by a quantitative perturbational molecular orbital treatment... 

The key piece of evidence for the rationalisation of the anomeric effect in terms of classical electrostatic dipole interactions has been the apparent existence of a reverse anomeric effect. Reversal of the sense of the dipole of the C-X bond, so that X now carries a net positive rather than negative charge, should, on the electrostatic picture, result in X having a more than ordinary tendency to be equatorial. The effect was first observed in glycosyl pyridinium salts and, in what at first sight seemed to be an elegant experiment, the steric demand of the bulky pyridinium salt was apparently eliminated as the source of the effect by the observation that tri-O-acetyl-ot-D-xylopyranosylimidazole changed from 65% to > 95% equatorial on addition of excess acid. Protonation of imidazole will have only a minor effect on its steric requirements, since protonation takes place at a remote site . ... 

Second-row heteroatoms are known to show a substantial anomeric effect. There appears to be evidence for a reverse anomeric effect in 2-aminotetrahydro-pyrans. ° It has been called into question whether a reverse anomeric effect exists at all. ° In 94, the lone-pair electrons assume an axial conformation and there is an anomeric effect. In 95, however, the lone-pair electron orbitals are oriented gauche to both the axial and equatorial oc-CH bond and there is no anomeric effect. ... 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

The influence of solvents in glycosylation reactions has been observed and discussed extensively already (1,4,74). For instance, the participation of ethers, when anomeric leaving-groups are removed under SNl-type conditions, results [because of the reverse anomeric effect (75,76)] in the genera-... 

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. 

When reacted with an alcohol in the presence of a catalytic amount of a strong acid, 3,4-dihydro-2/f-pyran yields a base-stable 2-alkoxytetrahydropyran (a cyclic acetal) (Scheme 4.13). The reaction is reversed if the acetal is treated with aqueous acid (see Section 3.3.4, page 54), so that this provides a simple way of protecting alcohols in syntheses where a strong base might otherwise deprotonate them. The conformational preferences of 2-alkoxytetrahydopyrans, mediated by the anomeric effect, were commented upon earlier (Section 1.5.3). 

This is exactly the reverse situation found in dealing with attachment of two methoxy groups or two fluorines (a acceptors and n donors) onto a tetrahedral carbon, also known as the anomeric effect, yet leads to exactly the same energetic consequences. 

Of particular interest is the influence of solvents under SNl-type conditions, as has been well studied for ethers [1,2,8]. The participation of ethers results, owing to the reverse anomeric effect [28] under SNl-type conditions, in the generation of equatorial oxonium ions (see Scheme 6, S = OEtj), which again favor the formation of thermodynamically more stable axial a- products [see Sec. 11I.B, Eqs. (6), (11), (16)]. 

A. J. Ratcliffe and B. Fraser-Reid, Generation of a-D-glucopyranosyl acetonitrilium ions. Concerning the reverse anomeric effect, J. Chem. Soc. Perkin Trans 7 747 (1990). 

On the other hand, it has been demonstrated that the a-D-glucopyranosyl aceto-nitrilium ions are stereospecifically generated from the corresponding oxocarbenium ions in dry acetonitrile [43-45]. These results indicate that the acetonjtrilium ions are axially oriented by an anomeric effect. Recently, it has been concluded from the conformational analyses of glucopyranosyl-ammonium and glucopyranosyl-imidazolium derivatives that the reverse anomeric effect does not exist [46,47]. 

C. L. Perrin and K. B. Armstrong, Conformadonal analysis of glucopyranosylammonium ions Does the reverse anomeric effect exist J. Am. Chem. Soc. 7/5 6825 (1993). 

M. A. Fabian, C. L. Perrin, and M. L. Sinnott, Absence of reverse anomeric effect Conformational analysis of glucosylimidazolium and glucosylimidazole, J. Am. Chem. Soc. 776 8398... 

In a probe for the presence of stereoelectronic effects in nucleophilic addition to 12 sterically unbiased ketones, calculations have identified subtle bond length differences in the C-Nu bond of the diastereomeric alcohol products, where Nu- = H-or Me-.304 The calculated differences are weak (<1%) but consistent the bond is longer in the major product, acting as a fossil record of the TS. Using microscopic reversibility, the easier bond to cleave (the longer one) is the easier to form. The effect bears comparison with the kinetic anomeric effect in sugars, where such bond length differences in calculation are borne out in X-ray crystal structures. 

The SM2/AM1 model was used to examine anomeric and reverse anomeric effects and allowed to state that aqueous solvation tends to reduce anomeric stabilization [58]. Moreover, SM2/AM1 and SM3/PM3 models were accounted for in calculations of the aqueous solvation effects on the anomeric and conformational equilibria of D-glucopy-ranose. The solvation models put the relative ordering of the hydroxymethyl conformers in line with the experimentally determined ordering of populations. The calculations indicated that the anomeric equilibrium is controlled primarily by effects that the gauche/trans 0-C6-C5-0 hydroxymethyl conformational equilibrium is dominated by favorable solute-solvent hydrogen bonding interactions, and that the rotameric equilibria were controlled mainly by dielectric polarization of the solvent [59]. On the other hand, Monte Carlo results for the effects of solvation on the anomeric equilibrium for 2-methoxy-tetrahydropyran indicated that the AM1/SM2 method tends to underestimate the hydration effects for this compound [60]. 

C. L. Perrin, Reverse anomeric effect fact or fiction Tetrahedron, 51 (1995) 11901-11935. 

Some the best-known work of Grein and his coworkers involves the development of methods for the calculation of hyperfine coupling constants.141 More recently the focus has shifted to calculating magnetic g-tensors from highly correlated wavefunctions. Grein s current interests include the study of stereoelectronic effects (such as the anomeric and reverse anomeric effects in acetal-like systems) in organic chemistry, a topic to which he has made important contributions.142... 

The anomeric effect, a stereoelectronic effect, is explained in terms of lone pair-lone pair repulsion, dipole-dipole interactions and by M.O. theory. The equatorial positions of a carbohydrate are favored by sterically demanding substituents. However, electronegative groups at the anomeric center prefer the axial position because of the stereoelectronic effects. This fact is known as the anomeric effect.13 If there is a positive charge at the anomer substituent of a carbohydrate, the equatorial conformation is preferred. To explain this result a reverse anomeric effect was proposed and first detected at A-(tt-glycopyranosyl)pyridinium ions 31 and 32.14... 

The existence of the reverse anomeric effect is controversial and seems to be rebuttet for pyranoses by NMR titration studies with (V-(D-glucopyranosyl)imidazole (33). Nitrogen-protonation of the imidazole should increase the proportion of the /(-anomer if there is a reverse anomeric effect. During and after titration no shift of the a /(-equilibrium to the /(-anomer was observed.15... 

Starting with phosphite 59 stannous triflate catalyzes the formation of an oxenium ion 60, which is stabilized by the solvent (61). The complex 61 is more favored than 63, justified by the reverse anomeric effect until now. But as it is shown there is no possibility for 61 to react in an SN2 reaction to 62. The intermediate 63 can be attacked by the alcohol functionality of the glycosyl acceptor, and with MeCN as leaving group you get 64. Ultimately the equilibrium between 61 and 63 shifts completely to 63. This kind of stereocontrol during a glycosylation is known as the nitrile effect.28... 

Another remarkable anomeric effect has been observed which has beCn named the reverse anomeric effect .37 By protonation of the imidazole-substituted D-xylo derivative the equilibrium shifts from mainly axial form to mainly equatorial form (Scheme 1.3). There are no changes in the steric requirement between the two compounds and therefore only a stereoelectronic explanation can account for this anomaly. Lemieux has... 

Some solvents may form complexes with the oxocarbenium ion intermediates, thereby affecting the anomeric outcome of a glycosylation. For example, diethyl ether is known to increase the a anomeric selectivity. Probably, diethyl ether participates by the formation of diethyl oxonium ion (Scheme 4.9a). The (3 configuration of this intermediate is favoured because of the operation of the reverse anomeric effect (see Chapter 1). Nucleophilic displacement with inversion of configuration will give an a glycoside. Recently, it was shown that a mixture of toluene and dioxane provides a more efficient participating solvent mixture. 

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