Hemiacetals anomeric effects

The hemiacetal thiol 75 (Fig. 13) gave on acid cyclization an equilibrium mixture of cis and trans monothioacetals 76 and 77 in a 1 1 ratio (63). If a value of 1.7 kcal/mol is accepted for the steric effects in 76 (two gauche forms of SCl XCHg = 0.8 kcal/mol and one gauche form of butane= 0.9 kcal/mol), the anomeric effect for the ether oxygen in 76 must also be equal to 1.7. 

As indicated in Scheme VII/32, cyclononanone (VII/165) is transformed into hydroperoxide hemiacetal, VII/167, which is isolated as a mixture of stereoisomers. The addition of Fe(II)S04 to a solution of VII/167 in methanol saturated with Cu(OAc)2 gave ( )-recifeiolide (VII/171) in quantitative yield. No isomeric olefins were detected. In the first step of the proposed mechanism, an electron from Fe2+ is transferred to the peroxide to form the oxy radical VII/168. The central C,C-bond is weakened by antiperiplanar overlap with the lone pair on the ether oxygen. Cleavage of this bond leads to the secondary carbon radical VII/169, which yields, by an oxidative coupling with Cu(OAc)2, the alkyl copper intermediate VII/170. If we assume that the alkyl copper intermediate, VII/170, exists (a) as a (Z)-ester, stabilized by n (ether O) —> <7 (C=0) overlap (anomeric effect), and (b) is internally coordinated by the ester to form a pseudo-six-membered ring, then only one of the four -hydrogens is available for a syn-//-elimination. [111]. This reaction principle has been used in other macrolide syntheses, too [112] [113]. 

The hemiacetal gives a locally planar oxonium ion that can add the phenol from the top or bottom face. The bottom face is preferred in this instance as axial C-O bonds are more stable in acetals because of the anomeric effect (p. 1130) and acetal formation is under thermodynamic control. 

The equiiibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals show the same response to structural features as the hydration reaction. Equilibrium constants for addition of methanol to acetaldehyde in both water and chloroform solution are near 0.8 The structural effects of the alcohol group have been examined. " Steric effects result in an order of CH3 C2H5 > (CH3)2CH > (013)30 for acetaldehyde hemiacetals. EWG substituents in the alcohol disfavor hemiacetal formation and this trend is believed to reflect the decreasing n tt hyperconjugation (anomeric effect, see Topic 1.2) as the substituents become more electron withdrawing. 

The cyclic hemiacetal (or hemiketal) can react with an alcohol to form an acetal (or ketal), called a glycoside. If the name pyranose or furanose is used, the acetal is called a pyranoside or a furanoside. The bond between the anomeric carbon and the alkoxy oxygen is called a glycosidic bond. The preference for the axial position by certain substituents bonded to the anomeric carbon is called the anomeric effect. If a sugar has an aldehyde, ketone, hemiacetal, or hemiketal group, it is a reducing sugar. 

The reverse anomeric effect occurs if the first atom bound to Cl is either positively charged (pyridinium) or carries a partial positive charge (car-bomethoxy). Mutarotation can be conveniently followed by measurements of H-NMR spectra. The hemiacetal methine proton appears at lower field than the other methine protons of the carbohydrate (e.g., at d = 4,97 ppm for an a-pyra-nose). Furthermore, large coupling constants (J = 6-9 Hz) indicate an axial-axial orientation of the protons at Cl and C2, whereas small coupling constants (J = 1-4 Hz) point to equatorial-equatorial or axial-equatorial relationships between these protons (Fig. 4.2.12). 

We saw in Chapter 2 that glucose can cyclize to form either the a ox hemiacetal. All of the substituents on the tetrahydropyran ring of glucose are equatorial except for the hemiacetal hydroxyl group, which may be either axial (for the a anomer) or equatorial (for the 6 anomer). If the conformational preferences of the tetrahydropyran ring are similar to those of cyclohexane, then an A value for OH of 0.87 in a protic solvent would predict that the axial anomer should comprise no more than 10% of the mixture. Experimentally, it has been determined that the a anomer is present to the extent of 34% of the equilibrium population of conformers. In the case of o-marmose, the a anomer (10) is the major isomer, and the )3 anomer (11) comprises only 32% of the equilibrium mixture. This preference for axial conformer in carbohydrates has been termed the anomeric effect. This term is also used for any system R-Y-C-X, where X is an electronegative atom and Y is an atom with at least one lone pair. 

The anomeric effect is widely believed to be caused by hyperconjugation. An axially oriented orbital associated with nonbonding electrons of the ring oxygen can overlap with a tr orbital of the axial exocyclic C—O hemiacetal bond. This effect is similar to that which helps cause the lowest energy conformation of ethane to be the anti conformation (Section 4.8). An anomeric effect will ffequendy cause an electronegative substituent, such as a hydroxyl or alkoxyl group, to prefer the axial orientation. 

Carbohydrate trichloroacetimidates have become very useful derivatives for the activation of the carbohydrate moiety. The carbohydrate can be readily transferred to form many types of glycosides [78]. Glycosides are readily formed by reaction of the hemiacetal hydroxyl with trichloroacetonitrile under base catalysis conditions. The p-anomer is rapidly and preferentially formed first as a favored kinetic product. Under base catalyzed conditions, however, it is slowly anomerized to give the a-anomer, which is the more stable thermodynamic product, due to the anomeric effect (reaction 4.63). Thus, either the a- or the P-anomer can be isolated in pure form and in high yield, depending on the length of time that the reaction is allowed to proceed. 

Hirai et al. [63] reported the use of this strategy for the synthesis of 5,5-benzaimulated spiroacetal 66 (Scheme 18). The major (doubly anomeric) isomer 66a arises from ring opening/closing of the hemiacetal 65, followed by oxypaUadation to give 69 (doubly stabilized by the anomeric effect). Subsequent syn elimination then provides 66a as the major isomer. 

The mild conditions offered by the approach of phosphitylation of the anomeric hemiacetals and subsequent oxidation of phosphites to phosphates suggest a very attractive alternative to the 1-0-lithiation method used in lipid A synthesis considering the complexity of the substrates. Indeed, an application of the phosphoramidite methodology was reported to be effective for the stereoselective instalment of the a-anomeric phosphate... 

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