Conformations, anomeric effect

As we shall see, the conformational anomeric effects can be assigned to stability difference between the various conformers that this ensemble of... 

The conformational anomeric effects design the contrasteric effects observed in acetals which render the more sterically encumbered gauche/ gauche conformers more stable than their anti/gauche and anti/anti conformers. Such effects were first evidenced by Jungins in 1905 and rediscovered by Edward in 1955 and by Lemieux and Chiu in 1958. They observed the higher stability of alkyl a-D-glucopyranosides in comparison with their (3-anomers (Fig. 5).8... 

Consequences of the conformational anomeric effect are largely expressed in monosaccharides and their derivatives. One recognizes the conformational endo-anomeric effect for pyranosides with a polar X group at C(l) (contrasteric electronic stabilization effect Fig. 7A) and conformational exo-anomeric effect for glycosides (acetals) in which the alkyl group of the exocyclic moiety is synclinal (Fig. 7B, C). 

The first interpretation of the conformational anomeric effect, given by Edward,2 invoked more favorable electrostatic interactions in the axial anomers than in the equatorial anomers of carbohydrates (Fig. 8). 

The rationalization of the conformational anomeric effect solely based on electrostatic interactions fails to account for these solvent effects. Another interpretation based on bond polarizability in 1,1-dialkoxyalkyl systems calls electronic transfer from a non bonding electron pair of one oxygen atom to the empty cr c 0 orbital from the other alkoxy substituent (Fig. 10).16... 

As conformational anomeric effects represent only a fraction (—1 to —3 kcal/mol) of the global enthalpic anomeric effect or gem-dioxy stabilizing effect (—6 to —17 kcal/mol), additional factors have to be taken into account. Depending on substitution, steric factors can affect the relative stability of acetal conformers. Dubois et al.2S have demonstrated that in furanose pyranose derivatives a bulky substituent at the furanose... 

The 2D-NMR NOESY correlations determined the absolute configuration (3S) for spirodioxocin 641a, which could adopt different conformations whose relative populations depended on steric factors, anomeric, and related effects and intramolecular //-bonding. In the preferred conformation of 641a, both endocyclic oxygen atoms were disposed in equatorial position relative to the other cycle and, therefore, such a structure was not stabilized by a conformational anomeric effect. The conformation (3Y)-641 a that disposed both endocyclic oxygen atoms in an axial position, which was stabilized by a double conformational anomeric effect, would imply chair-chair conformation for... 

Hall and coworkers54) estimated the conformational equilibrium for both cis and trans isomers of poly-6,8-dioxabicyclo[3.2.1]octane and 2,6-dioxabicyclo[2.2.2]octane by the interplay of two factors (1) the familiar preference of alkyl substituents to exist in the equatorial conformation and (2) the preference of the alkoxy group for the axial conformation (anomeric effect). The numerical parameters (kJ/mol) used for the calculations were174-175) OCH3ax - Hax, 1.9 CH3ax - Hax, 3.8 CH3ax - OCH3ax, 10 OCH - (anomeric effect), 5.4. 

A proper analysis of the above results has to take into consideration the particular conformational properties of DFAs, which are governed by stereoelectronic effects. The relatively flexible 1,4-dioxane central ring adopts a chair or boat conformation for dispiro-DFAs having different or identical configuration at the anomeric centers, respectively, in order to place the oxygen substituents in pseu-doaxial orientation, fitting the conformational anomeric effect [47], and the carbon substituents in pseudoequatorial position (Fig. 2). 

Abe H, Shuto S, Matsuda A (2001) Highly a- and P-selective radical C-glycosylation reactions using a controlling anomeric effect based on the conformational restricrion strategy. A study on the conformation - anomeric effect - stereoselectivity relationship in anomeric radical reactions. J Am Chem Soc 123 11870-11882... 

Roversi E, Scopelliti R, Solari E, Estoppey R, Vogel P, Brafia P, Menendes B, Sordo JA. The hetero-Diels-Alder addition of sulfur dioxide to 1-fluorohuta-l,3-dienes the sofa conformations preferred by 6-fluorosultines (6-fluoro-3,6-dihydro-l,2-oxathiin-2-oxides) enjoy enthalpic and conformational anomeric effects. Chem. Eur. J. 2002 8... 

The Ueno-Stork reaction is a radical cyclization of the a-haloacetal of an aUylic alcohol that provides substituted tetrahydrofuran and y-lactone derivatives. The chiral center of the aUylic moiety can control the stereochemical outcome, and the stereoselectivity may also be affected by the conformational anomeric effect. The Ueno-Stork radical cyclization has been applied in the synthesis of (-l-)-eldanolide (Scheme 25.22)," the pheromone of the male African sugarcane stem borer Eldana saccharina, in which bromoacetal 49 evolves to 50. The stereochemical outcome of these reactions is rationalized by a chair-like transition state, in which the adopted conformation maximizes the anomeric effect of the acetal center. 

An electronegative substituent adjacent to a ring oxygen atom also shows a preference for an axial orientation. This is known as the anomeric effect , and is particularly significant to the conformations of carbohydrates (B-71MI20100, B-83MI20100). 

Compounds in which conformational, rather than configurational, equilibria are influenced by the anomeric effect are depicted in entries 4—6. Single-crystal X-ray dilfiaction studies have unambiguously established that all the chlorine atoms of trans, cis, ira j-2,3,5,6-tetrachloro-l,4-dioxane occupy axial sites in the crystal. Each chlorine in die molecule is bonded to an anomeric carbon and is subject to the anomeric effect. Equally striking is the observation that all the substituents of the tri-0-acetyl-/ -D-xylopyranosyl chloride shown in entry 5 are in the axial orientation in solution. Here, no special crystal packing forces can be invoked to rationalize the preferred conformation. The anomeric effect of a single chlorine is sufficient to drive the equilibrium in favor of the conformation that puts the three acetoxy groups in axial positions. 

Several structural factors have been considered as possible causes of the anomeric effect. In localized valence bond terminology, it can be recognized that there will be a dipole-dipole repulsion between the polar bonds at the anomeric carbon in the equatorial conformation. This dipole-dipole interaction is reduced in the axial conformation, and this factor probably contributes to the solvent dependence of the anomeric effect. 

The anomeric effect is also present in acyclic systems and stabilizes conformations that allow antiperiplanar (ap) alignment of the C—X bond with a lone-pair orbital of the heteroatom. Anomeric effects are prominent in determining the conformation of acetals and a-alkoxyamines, as well as a-haloethers. MO calculations (4-3IG) have found 4kcal/mol as the difference between the two conformations shown below for methoxy-methyl chloride. ... 

The preference for the gauche arrangement is an example of the anomeric effect. An oxygen lone pair is anti to fluorine in the stable conformation but not in the unstable conformation. 

Even molecules as simple as dimethoxymethane give evidence of anomeric effects. The preferred conformation of dimethoxymethane aligns each C—O bond with a lone-pair orbital of the adjacent oxygen. ... 

In cyclic systems such as 1, the dominant conformation is the one with the maximum anomeric effect. In the case of 1, only conformation lA provides the preferred antiperiplanar geometry for both oxygens. Antiperiplanar relationships are indicated by including lone pairs in the oxygen orbitals. Other effects, such as torsional strain and nonbonded repulsion, contribute to the conformational equilibrium, of course. Normally, a value of about 1.5 kcal/mol is assigned to the stabilization due to an optimum anomeric interaction in an acetal. 

The six-membered rings 8.12a and 8.12b adopt chair conformations with all three halogen atoms in axial positions. This arrangement is stabilized by the delocalization of the nitrogen lone pair into an S-X a bond (the anomeric effect) All the S-N distances are equal within experimental error [ld(S-N)l = 1.60 (8.12a)/ 1.59 A (8.12b) ]. 

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. 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

It is interesting to speculate that asymmetric induction may be the consequence of the exo anomeric effect, a stereoelectronic effect that favors the conformation 5 that places the aglycone O-C bond antiperiplanar to the pyran C(1) —C(2) bond7fi. Related asymmetric induction has also been observed in aldehyde addition reactions of the related, but racemic, pinacol (Z)-y-(tetrahydropyranyloxy)allylboronate49. As indicated in the examples above, however, the level of diastereoselectivity is modest and the only application in asymmetric synthesis is Wuts exo-brevicomin synthesis75. 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

Polymerization of 4-bromo-6,8-dioxabicyclo[3.2.1 ]octane 2 7 in dichloromethane solution at —78 °C with phosphorus pentafluoride as initiator gave a 60% yield of polymer having an inherent viscosity of 0.10 dl/g1. Although it is not described explicitly, the monomer used seems to be a mixture of the stereoisomers, 7 7a and 17b, in which the bromine atom is oriented trans and cis, respectively, to the five-membered ring of the bicyclic structure. Recently, the present authors found that pure 17b was very reluctant to polymerize under similar conditions. This is understandable in terms of a smaller enthalpy change from 17b to its polymer compared with that for 17a. In the monomeric states, 17b is less strained than 17a on account of the equatorial orientation of the bromine atom in the former, whereas in the polymeric states, the polymer from 17b is energetically less stable than that from 17a, because the former takes a conformation in which the bromine atom occupies the axial positioa Its flipped conformation would be even more unstable, because the stabilization by the anomeric effect is lost, in addition to the axial orientation of the methylene group. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

In 1991, an important paper was published by Bock et a/.84 that described the steric and electronic effects on the formation of the dispiroketal dihexulose dianhydrides. The authors described the conformation of six dihexulose dianhydrides, as determined by X-ray crystallography or NMR spectroscopy. They concluded that these conformations are dictated by the anomeric and exo-anomeric effects. Thus, the dihexulose dianhydrides are disposed to adopt conformations that permit operation of these effects—even if this results in the dioxane ring having a boat conformation or all three substituents on one pyranose ring being axial. 

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