Reverse Anomeric Effect Research Articles

Exploring and Re-Assessing Reverse Anomeric Effect in 2-Iminoaldoses Derived from Mono- and Polynuclear Aromatic Aldehydes.

A curious and noticeable structural feature in Schiff bases from 2-aminoaldoses is the fact that imino tautomers arranged equatorially in the most stable ring conformation exhibit a counterintuitive reverse anomeric effect (RAE) in the mutarotational equilibrium, i.e., the most stable and abundant anomer is the equatorial one (β). As shown by our very recent research, this effect arises from the total or partial inhibition of the exo-anomeric effect due to the presence of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen in the axial anomer (α). When the Schiff base adopts either an enamine structure or the imino group is protonated, the exo-anomeric effect is restored, and the axial α-anomer becomes the most stable species. Although the intramolecular H-bonding should appropriately be interpreted as a genuine stereoelectronic effect, the magnitude of the RAE could be affected by other structural parameters. Herein and through a comprehensive analysis of benzylidene, cinnamylidene, naphthalene, phenanthrene, and anthracene aldehydes, we show the robustness of the RAE effect, which is similar in extent to simple aldehydes screened so far, irrespective of the size and/or hydrophobicity of the substituent at the nitrogen atom.

A True Reverse Anomeric Effect Does Exist After All: A Hydrogen Bonding Stereocontrolling Effect in 2-Iminoaldoses.

The reverse anomeric effect is usually associated with the equatorial preference of nitrogen substituents at the anomeric center. Once postulated as another anomeric effect with explanations ranging from electrostatic interactions to delocalization effects, it is now firmly considered to be essentially steric in nature. Through an extensive research on aryl imines from 2-amino-2-deoxyaldoses, spanning nearly two decades, we realized that such substances often show an anomalous anomeric behavior that cannot easily be rationalized on the basis of purely steric grounds. The apparent preference, or stabilization, of the β-anomer takes place to an extent that not only neutralizes but also overcomes the normal anomeric effect. Calculations indicate that there is no stereoelectronic effect opposing the anomeric effect, resulting from the repulsion between electron lone pairs on the imine nitrogen and the endocyclic oxygen. Such data and compelling structural evidence unravel why the exoanomeric effect is largely inhibited. We are now confident, as witnessed by 2-iminoaldoses, that elimination of the exo-anomeric effect in the α-anomer is due to the formation of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen, thereby accounting for a true electronic effect. In addition, discrete solvation may help justify the observed preference for the β-anomer.

Leveraging Stereoelectronic Effects in Biofilm Eradication: Synthetic β-Amino Human Milk Oligosaccharides Impede Microbial Adhesion As Observed by Scanning Electron Microscopy.

Alongside Edward, Lemieux was among the earliest researchers studying negative hyperconjugation (i.e., the anomeric effect) or the preference for gauche conformations about the C1-O5 bond in carbohydrates. Lemieux also studied an esoteric, if not controversial, theory known as the reverse anomeric effect (RAE). This theory is used to rationalize scenarios where predicted anomeric stabilization does not occur. One such example is the Kochetkov amination where reducing end amines exist solely as the β-anomer. Herein, we provide a brief account of Lemieux's contributions to the field of stereoelectronics and apply this knowledge toward the synthesis of β-amino human milk oligosaccharides (βΑ-HMOs). These molecules were evaluated for their ability to inhibit growth and biofilm production in Group B Streptococcus (GBS) and Staphylococcus aureus. While the parent HMOs lacked antimicrobial and antibiofilm activity, their β-amino derivatives significantly inhibited biofilm formation in both species. Field emission gun-scanning single electron microscopy (FEG-SEM) revealed that treatment with β-amino HMOs significantly inhibits bacterial adherence and eliminates the ability of both microbes to form biofilms.

Theoretical study on the anomeric effect in α-substituted tetrahydropyrans and piperidines

Conformational effects, including some controversial examples, have been reported in this work for 2-substituted tetrahydropyrans and piperidines, and for the respective protonated compounds [substituent = F, OH, OCH3, NH2, NHCH3 and N(CH3)2]. Hyperconjugation plays a major role in most cases, either due to endo or exo-anomeric interactions, especially when nitrogen is the electron donor to an antiperiplanar σ* orbital. This interaction also seems to contribute for the Perlin and reverse fluorine Perlin-like effects, which are related to the relative magnitude of 1JC,H and 1JC,F coupling constants, respectively, in axial and equatorial conformers. However, the preference for an equatorial conformation appears when a hydrogen or methyl group of the substituent faces the ring, increasing the steric repulsion, even if concomitant with a hyperconjugative interaction in the axial isomer, such as for the well-known 2-aminotetrahydropyran. Unlike some reports in the literature, the gas phase 2-hydroxypiperidine experiences the herein called reverse anomeric effect, although the highly stabilizing nN → σ*C-O interaction in the axial isomer. Overall, steric effects should be taken into account when deciding for the normal or reverse anomeric effects as determinant factors of the stereochemical control of carbohydrate-like molecules.

The Logic behind a Physical–Organic Chemist’s Research Topics

Although my research has no common theme or defining area, a coherence connects the diverse topics insofar as one project leads logically to another. Thus, studies on mechanisms of hydrogen exchange in amides and amidines led to the influence of hydrogen bonding and to NMR methods for chemical kinetics, including 2D-EXSY spectroscopy. Another connection was the OH--catalyzed NH exchange in amines that had supported the hypothesis of stereoelectronic control. We therefore analyzed that hypothesis critically, tested it, found counterexamples, and proposed an alternative hypothesis. We next addressed one-bond NMR coupling constants in ethers and the reverse anomeric effect. The latter studies required a highly accurate NMR titration method that we developed to measure the additional steric bulk resulting from protonation of a substituent. This method is also applicable to measuring secondary isotope effects on acidity, and we could demonstrate that they arise from n-σ* delocalization, not from an inductive effect. Other studies included kinetic isotope effects for both dissociation and H exchange of aqueous NH4+, for C-N rotation in amides, and for a hydride transfer. The role of hydrogen bonding led us to the rotation of NH4+ within its solvent cage and then to the symmetry of hydrogen bonds.

Reverse Anomeric Effect in Large-Amplitude Pyridinium Amide-Containing Mannosyl [2]Rotaxane Molecular Shuttles.

The reverse anomeric effect (RAE) was investigated in different mannosyl [2]rotaxane molecular shuttle isomers that contain dibenzo-24-crown-8 (DB24C8) as the macrocycle, and anilinium and pyridinium amide as molecular stations. The switching on or off of the RAE was possible depending on both the pyridinium amide motif and the localization of the DB24C8 along the thread. The (1) C4 mannopyranosyl chair-like conformation was observed in all the non-interlocked molecules because the anomeric carbon of the mannose is linked to the positively charged nitrogen of the pyridinium unit. In the protonated rotaxanes, the (1) C4 chair conformation of the mannose end remains because the DB24C8 resides around the best anilinium station, which is located at the other end of the axle. Upon deprotonation of the anilinium, the DB24C8 shuttles with a large-amplitude motion toward the pyridinium amide stations, where it interacts in a different fashion depending on the pyridinium motif. In one molecular shuttle, the RAE could be switched on or off with control at one end of the encircled thread upon protonation/deprotonation of the other end, through shuttling of the DB24C8.

Syntheses of sugar poly(orthoesters) through reverse anomeric effect.

High molecular weight sugar poly(orthoesters) were synthesized through reverse anomeric effect (RAE). We demonstrated that when RAE-enabled promoters, such as 4-(dimethylamino)pyridine (DMAP), triphenylphosphine (TPP) or imidazole, were employed, efficient polymerizations were achieved, giving sugar poly(orthoesters) with molecular weights up to 18 kDa.

Half a century of research, teaching, service

This is a summary of the research of Charles L. Perrin and his coworkers in the areas of aromatic mercuration, vibronic borrowing, ipso factors in electrophilic aromatic substitution, malonic anhydrides, mechanisms of proton exchange in amides, stereoelectronic control, the so‐called reverse anomeric effect, an NMR titration method for highly accurate measurement of relative acidities, secondary deuterium isotope effects on acidity, symmetry of hydrogen bonds in solution, and nucleophilic addition to a para‐benzyne diradical, along with Perrin's contributions to teaching and to service. Copyright © 2014 John Wiley & Sons, Ltd.

SnCl4- and TiCl4-Catalyzed Anomerization of Acylated O- and S-Glycosides: Analysis of Factors That Lead to Higher α:β Anomer Ratios and Reaction Rates

The quantification of factors that influence both rates and stereoselectivity of anomerization reactions catalyzed by SnCl(4) and TiCl(4) and how this has informed the synthesis of α-O- and α-S-glycolipids is discussed. The SnCl(4)-catalyzed anomerization reactions of β-S- and β-O-glycosides of 18 substrates followed first order equilibrium kinetics and k(f) + k(r) values were obtained, where k(f) is the rate constant for the forward reaction (β → α) and k(r) is the rate constant for the reverse reaction (α → β). Comparison of the k(f) + k(r) values showed that reactions of glucuronic acid or galacturonic acid derivatives were ∼10 to 3000 times faster than those of related glucoside and galactopyranoside counterparts and α:β ratios were generally also higher. Stereoelectronic effects contributed from galacto-configured compounds were up to 2-fold faster than those of corresponding glucosides. The introduction of groups, including protecting groups, which are increasingly electron releasing generally led to rate enhancements. The anomerization of S-glycosides was consistently faster than that of corresponding O-glycosides. Reactions were generally faster for reactions with TiCl(4) than those with SnCl(4). Anomeric ratios depended on the Lewis acid, the number equivalents of the Lewis acid, temperature, and substrate. Very high ratios of α-products for both O- and S-glucuronides were observed for reactions promoted by TiCl(4); for these substrates TiCl(4) was superior to SnCl(4). Anomeric ratios from anomerization of S-glucosides were higher with SnCl(4) than with TiCl(4). The dependence of equilibrium ratio on Lewis acid and the number of equivalents of Lewis acid indicated that the equilibrium ratio is determined by a complex of the saccharide residue bound to the Lewis acid and not the free glycoside. The high α:β ratios observed for anomerization of both O- and S-glycuronic acids can be explained by coordination of the C-1 heteroatom and C-6 carbonyl group of the product to the Lewis acid, which would enhance the anomeric effect by increasing the electron-withdrawing ability of the anomeric substituent and lead to an increase in the proportion of the α-anomer. Such an observation would argue against the existence of a reverse anomeric effect. Support for a chelation-induced endocyclic cleavage mechanism for the anomerization is provided by the trapping of a key intermediate. The data herein will help predict the tendency of β-glycosides to undergo anomerization; this includes cases where 1,2-trans glycosides are initial products of glycosidation reactions catalyzed by TiCl(4) or SnCl(4).

Application of the additivity of group energies to understand conformational preference: the anomeric effect

The conformational preference in normal and reverse anomeric effects is analyzed by taking advantage of the known additivity and transferability of functional group energies defined by the gradient of the electron density. As the anomeric effect has an energetic origin and every change in the electron density produces an energetic change, an explanation of this phenomenon should be based on the density changes taking place in a conformational equilibrium. The total energy of substituted cyclohexanoids is partitioned into ring and substituent contributions and the preferred conformation is the result of a balance between them. This new alternative approach allows understanding of the anomeric effect in terms of group energy contributions. In general, the most stable conformer in both the anomeric and reverse anomeric effects is that where the ring transfers charge to the heteroatom in the substituent during the process.

Synthesis of α- and β-Glycosyl Isothiocyanates via Oxazoline Intermediates

A practical synthesis of acylated glycosyl isothiocyanates from sugar oxazolines, by reaction with thiophosgene, is reported. In the absence of any additive, the reaction is governed by the reverse anomeric effect, leading to the equatorially oriented isothiocyanate. However, in the presence of copper(II) chloride, the reaction proceeds preferentially with retention of the configuration at the anomeric center, providing the axial anomer as the major product. Noteworthy, this strategy allows accessing per-O-acetylated glycopyranosyl isothiocyanates with 1,2-cis relative configuration (e.g., the alpha-anomer in the D-gluco and D-galacto series), a problem that was outside the scope of previous methodologies.

Absence of Reverse Anomeric Effect in Furanosides

A series of conformationally restricted N-"furanosides" has been synthesized, where the carbons of the tetrahydrofuran ring are kept in one plane by a rigid norbornane skeleton, permitting only the ring oxygen to move above or below the tetrahydrofuran ring plane. This causes the substituents of the anomeric carbon to occupy a pseudoaxial or a pseudoequatorial position. On protonation of these "norbornane-furanosides" with trifluoromethanesulfonic acid, all three compounds exhibited decreasing coupling constants for the anomeric proton, indicating a shift toward the pseudoaxial conformation. The coupling constant measurements were supported by volume integration of NOESY cross-peaks, which also showed a change toward the pseudoaxial conformation upon protonation of the nitrogen. These results provide no evidence for the so-called reverse anomeric effect; on the contrary they are in full agreement with a small normal anomeric effect.

Some recent developments in stereoelectronic theory. Reevaluations of ALPH and the reverse anomeric effect

A critique of objections to the 'antiperiplanar lone pair hypothesis' (ALPH) and the 'reverse anomeric effect' (RAE) is presented. Whilst early fears that ALPH is incompatible with the Curtin-Hammett principle (CHP) were apparently unfounded, objections to ALPH based on the reactions of cyclic hemiorthoesters and amidinium salts are debatable. (The unreactivity of Kirby's bicyclic bridgehead acetal supports ALPH convincingly.) Objections to RAE were based on its apparent incompatibility with ALPH, studies on several models indicating (dubiously) the existence of a weak anomeric effect rather than RAE. However, this may well suggest that a normal anomeric effect is being offset by RAE. This apparently indicates different bases for the ground state and kinetic anomeric effects: the classical 'electrostatic gauche repulsive interaction' (EGRI) and the 'orbital interaction' (OI) respectively. The evidence against free oxocarbenium ions, but favouring the ion pair and the 'exploded transition state' (ETS) models apparently raises the question 'Whither ALPH?'. A rigorous application of the CHP to the stereochemistry of displacements at glycosyl anomeric centres, indicates that the alpha anomers react retentively via ion pairs, whereas the beta anomers react with inversion via the ETS. (A substantial reassessment of the 'in situ anomerisation technique' is also indicated.)

Anomeric effects versus steric hindrance to ionic solvation in protonated glucosylanilines and cyclohexylanilines.

The so-called reverse anomeric effect is the preference of cationic substituents for the equatorial position on a pyranose ring, but it is not consistent with current theories of molecular structure or with previous studies designed to test it. To probe this further, the N-protonation-induced shifts of the anomeric equilibrium in a series of N-(tetra-O-methylglucopyranosyl)anilines have been measured with high precision through an NMR titration method that compares basicities of alpha and beta anomers in a mixture of the two. For comparison, the N-protonation-induced shifts of the cis/trans equilibrium in N-(4-tert-butylcyclohexyl)anilines have also been measured by this same method. In both series, there is a shift of the equilibrium toward equatorial upon N-protonation, consistent with steric hindrance to ionic solvation. This shift is smaller for the glucosylanilines than for the cyclohexylanilines, consistent with an enhancement of the normal anomeric effect that counters the steric hindrance and reduces the shift toward the equatorial beta anomer. Moreover, the shift toward equatorial increases slightly but detectably with electron-withdrawing substituents on the cyclohexylaniline, which fine-tune the steric hindrance to ionic solvation. In contrast, the shift decreases for the glucosylanilines. This is consistent with an enhancement of the normal anomeric effect due to a more localized positive charge, rather than with a reverse anomeric effect. These results thus define the substituent dependence of the anomeric effect.

An examination of the purported reverse anomeric effect beyond acetylated N-xylosyl- and N-glucosylimidazoles.

Syntheses of six new N-(pentopyranosyl)imidazoles have been achieved, and their conformations were observed with and without protonation. A decisive decrease in J(5',4), consistent with stabilization of the 1C4 conformations, was clearly observed for three N-(pentopyranosyl)imidazoles. As well, no reverse anomeric stabilization was observed for N-(2,3,4-tri-O-acetyl-alpha-D-lyxopyranosyl)imidazole upon protonation. It is suggested that the previous observations of the reverse anomeric effect were due to the slight increase in steric bulk of the imidazole aglycone upon protonation, along with favorable dipolar interactions between ring substituents, and not by a reverse of the anomeric effect.

Explorations of the origins of the reverse anomeric effect of the monosaccharides using the QVBMM (molecular mechanics) force field

The molecular modeling program STR3DI32.EXE, and its molecular mechanics module, QVBMM, were used to simulate and evaluate the stereo-electronic effects in the pyranoid analogs of the derivatives of monosaccharides that are known to display the reverse anomeric effect. This study has confirmed the importance of bond dipoles, particularly hydrogen bonding, in these effects. This study also holds considerable implications for unraveling the chemistry of glycoside formation and hydrolysis.

Anab initio interpretation in gas phase and aqueous solution of the generalized anomeric effect in R?O?CR2?NR2 (R = H, CH3)

The conformational stability of aminomethanol and its methylated derivatives has been investigated by means of ab initio methods in the gas phase and aqueous solution. Among the computational levels employed, HF/6-31G**//HF/6-31G** calculations correctly describe the conformational features of this series of compounds, and agree well with the results obtained using larger basis sets and including ZPE or electron correlation corrections. Calculated energies and geometries follow the known trends associated to the generalized anomeric effect. Thus, the most stable conformers exhibit preferences for the trans orientations of the LpN CO and LpOCN moieties. However, reverse anomeric effects are observed when a methyl group is bonded to the oxygen, because the LpOCN unit prefers a gauche orientation (that is, trans MeOCN). The natural bond orbital (NBO) method was employed to explain the cited conformational preferences. According to the NBO results, trans arrangements are preferred because the stabilization due to charge delocalization is more important than electrostatic and steric contributions. This explanation agrees with the conclusions obtained by other independent procedures based on energy decomposition schemes. The NBO method was also used to explain the origin of the rotational barriers around the C O and CN bonds in terms of the balance between unfavorable hyperconjugation and electrostatic and steric effects. Changes in conformational stability caused by methylations in different molecular positions were also explained by the influence of the methyl groups on lone-pair delocalization and on steric effects. Finally, the effect of solvation was studied by means of the ab initio PCM method, and the significant changes on relative energies found were analyzed. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 462–477, 2000

Role of the anomeric effect in methanediamines in the gas phase and aqueous solutions

An ab initio study of methylenediamine and several methylated derivatives in the gas phase and aqueous solution was performed. The conformational preferences can be considered adequately described at the HF/6-31G**//HF/6-31G** level, because these results agree with those obtained using larger basis sets and including ZPE and electron correlation. The energy ordering is clearly dependent on the number and position of the methyl groups present in a molecule. For a first set of the compounds, the energies obtained were interpreted in terms of the anomeric effect because the favored conformers show two or one anti orientation between the nitrogen lone pair and the CN polar bond. Reverse anomeric effects were found for a second set of compounds. The NBO analysis was used to interpret these energetic tendencies and the rotational barrier around the NC bonds. Thus, the preference for the anti-LpNCN orientations is mainly due to charge delocalization, always stronger than the electrostatic and steric contributions included in the Lewis term. However, the origin for the reverse anomeric effect may be related to the steric hindrance associated with the methylation. The influence of water on the conformational preferences was evaluated by means of the PCM method. Contrary to expectation, the anomeric effect is not reduced in water, and the most stable conformers in the gas phase are maintained in solution. The electrostatic term of the free solvation energy is the main responsible of the energetic changes, and depends strongly on local solute–solvent interactions. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 135–150, 2001

Is there a generalized reverse anomeric Effect? substituent and solvent effects on the configurational equilibria of neutral and protonated N-arylglucopyranosylamines and N-aryl-5-thioglucopyranosylamines

The effects of substitution and solvent on the configurational equilibria of neutral and protonated N-(4-Y-substituted-phenyl) peracetylated 5-thioglucopyranosylamines (Y = OMe, H, CF(3), NO(2)) 1-4 and N-(4-Y-substituted-phenyl) peracetylated glucopyranosylamines (Y = OMe, H, NO(2)) 9-11 are described. The configurational equilibria were determined by direct integration of the resonances of the individual isomers in the (1)H NMR spectra after equilibration of both alpha- and beta-isomers. The equilibrations of the neutral compounds 1-4 in CD(3)OD, CD(3)NO(2), and (CD(3))(2)CO were achieved by HgCl(2) catalysis and those of the neutral compounds 9-11 in CD(2)Cl(2) and CD(3)OD by triflic acid catalysis. The equilibrations of the protonated compounds in both the sulfur series (solvents, CD(3)OD, CD(3)NO(2), (CD(3))(2)CO, CDCl(3), and CD(2)Cl(2)) and oxygen series (solvents, CD(2)Cl(2) and CD(3)OD) were achieved with triflic acid. The substituent and solvent effects on the equilibria are discussed in terms of steric and electrostatic effects and orbital interactions associated with the endo-anomeric effect. A generalized reverse anomeric effect does not exist in neutral or protonated N-aryl-5-thioglucopyranosylamines and N-arylglucopyranosylamines. The anomeric effect ranges from 0.85 kcal mol(-)(1) in 2 to 1.54 kcal mol(-)(1) in 10. The compounds 1-4 and 9-11 show an enhanced endo-anomeric effect upon protonation, ranging from 1.73 kcal mol(-)(1) in 2 to 2.57 kcal mol(-)(1) in 10. We estimate the increase in the anomeric effect upon protonation of 10 to be approximately 1.0 kcal mol(-)(1). However, this effect is offset by steric effects due to the associated counterion which we estimate to be approximately 1.2 kcal mol(-)(1). The values of K(eq)(axial-equatorial) in protonated 1-4 increase in the order OMe < H < CF(3) < NO(2), in agreement with the dominance of steric effects (due to the counterion) over the endo-anomeric effect. The values of K(eq)(axial-equatorial) in protonated 9-11 show the trend OMe > H < NO(2) that is explained by the balance of the endo-anomeric effect and steric effects in the individual compounds. The trends in the values of the C(1)-H(1) coupling constants for 1-4 and the corresponding deacetylated compounds 5-8 as a function of substituent and alpha- or beta-configuration are discussed in terms of the Perlin effect and the interplay of the endo- and exo-anomeric effects.

Absence of Reverse Anomeric Effect in Glycosylimidazoles

The so-called reverse anomeric effect is the preference of cationic substituents for the equatorial position on a pyranose ring, but it is not consistent with theories of molecular structure. To reinvestigate this, we have measured the N-protonation-induced shifts of the anomeric equilibrium in N-(glycopyranosyl)imidazoles and their tetra-O-acetyl derivatives 1−3 with high precision through an NMR titration method that is applicable to a mixture of α and β anomers. We find a ΔΔG°β→α that is almost always negative, corresponding to a greater preference for the axial position of a protonated imidazolyl group than of an unprotonated group. This preference counters a small steric effect, arising from hindrance to ionic solvation, that has been measured independently in N-(4-tert-butylcyclohexyl)imidazoles 4. These results are exactly opposite to what is expected from the reverse anomeric effect. We conclude that there is no firm evidence for this effect.