Anomeric radical effect

A major strategy for the preparation of branched-chain sugars is the intermolecular addition of nonanomeric carbohydrate-based radicals to a 7t-system. Since no special electronic factors, such as radical anomeric effects, are present, the stereoselectivity is controlled sterically, and the stereochemistry of the substituents adjacent to the radical center mainly governs the stereochemical control. Representative results are summarized in Scheme 23. 

Despite the usual loss of optical activity noted above, asymmetric radicals can be prepared in some cases. For example, asymmetric nitroxide radicals are known. An anomeric effect was observed in alkoxy radical (31), where the ratio of 31a/31b was 1 1.78. ... 

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 stereochemistry of the reaction of glycosyl radicals is strongly influenced by the anomeric effect. Glucopyranosides and manno-pyranosides afford stereo selectively the a-C-glycosyl compounds whereas in furanosidic structures the stereochemistry is not always predictable. 

The influence of the classical anomeric effect and quasi-anomeric effect on the reactivity of various radicals has been probed. The isomer distribution for the deu-teriation of radical (48) was found to be selective whereas allylation was non-selective (Scheme 37). The results were explained by invoking a later transition state in the allylation, thus increasing the significance of thermodynamic control in the later reactions. Radical addition to a range of o -(arylsulfonyl)enones has been reported to give unexpected Pummerer rearrangement products (49) (Scheme 38).A mechanism has been postulated proceeding via the boron enolate followed by elimination of EtaBO anion. 

In contrast, the mannosyl radical 8 does not undergo such a conformational change, and the observed a-attack results from the shielding effect of the axial C-2 substituent in the chair conformation and the stereoelectronic effects mentioned earlier. In radicals 7b and 8 the C-O bonds adjacent to the radical center are coplanar with the singly occupied orbital. This reminds us of the anomeric effect in which an interaction between the nonbonding electron pair of the ring oxygen and the LUMO of the C-O bond stabilizes the conformation. 

Using a binary sensitizing system (phenanthrene P/DCNB /7-dicyanobenzene) in acetonitrile solution, O-aryl glycosides are transacetalized with alcohols after generation of aromatic radical cations [23], According to kinetic anomeric effects, the a-side attack of nucleophiles to cyclic oxocarbenium ions follows scheme 9. 

The marked stereoselectivity of these radical reactions must be ascribed to the effect of the bulk of the protecting groups. However, the radicals that were manipulated may have also shown an anomeric effect due to the vicinal oxygen. In a furanose sugar it is not easy to evaluate the anomeric effect without ESR, and also, the molecules concerned have two fused five-membered rings. This fixes the conformation into a V-shape. Such molecules are well known to have exo-reactivity and the formation of endo-bonds is difficult. All these effects may be acting together to make this nucleoside chemistry especially stereospecific. 

Glycosides." The construction of p-glycosides has relied heavily on the anomeric effect (equatorial C2-acetoxy substituent). A recent approach relies on generation of a radical at an alkoxy-substituted anomeric position. The precursors (1) can be obtained as shown in equation (I). The same strategy can be applied to construction of (J-linked disaccharides. 

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]. 

These results are in good agreement with a rapid addition of an electrophilic radical72 (generated by oxidation of azide ion in situ) to C-2 of the electron-rich double bond, affording an anomeric radical stabilized in the a configuration by the anomeric effect. Further homolytic reaction with diphenyl diselenide affords the a-selenoglycoside. 

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