The kinetic anomeric effect

The role of the kinetic anomeric effect was demonstrated by the difference in diastereoselectivities observed for the addition of LiP03Me2 to IV-glycosylnitrone 51 and to the deoxy analogue 52. In TFIF, the difference in diastereoselectivities corresponds to a value of 1.1 kcal/mol while in CH2CI2 it gives a value of 0.6 kcal/mol. Moreover the deoxy derivative 52 undergoes a slower reaction than its parent glycosylnitrone 51. 

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. 

Generally, the products derived from the open-chain form are insignificant in the reaction mixture and stereocontrol between the anomeric forms can be achieved. It was observed that the anomeric oxygen in the equatorial alkoxide 276 has enhanced nucleophilicity compared with the axial [284]. Often referred to as the kinetic anomeric effect, this phenomenon can govern the diastereoselective formations of the equatorial glycosides [579]. The anomeric effect, however, favors the formation of the thermodynamically more stable axial glycosides and chelation control can also play a role in determining anomeric stereoselectivity. 

Huber, R, Vasella, A, The kinetic anomeric effect. Additions of nucleophiles and of dipolarophiles to A-glycosylnitrones and to A-pseudoglycosylnitrones, Tetrahedron, 46, 33-58, 1990. 

Stereochemical control in 0-alkylative /3-glycosylation relies on the kinetic anomeric effect [110] namely, that the oxyanion derived from a reducing sugar is more reactive in its 8-ori-ented form 71B than the corresponding a-anion 71A which should be more abundant. This tactic has met with partial success in cases of reactive substrate [111] (O Scheme 38). For example, reaction of 72 with a primary triflate in THF in the presence of NaH afforded the 8-glycoside in 62% yield. 

Many examples of stereoelectronic effects have been proposed in numerous areas of organic chemistry. The textbook example is perhaps the requirement for the anti conformation of the electrons of the scissile C—H bond with the leaving group in the E2 elimination reaction. However, over the past decade, the term stereoelectronic effect has become synonymous with an effect otherwise termed the kinetic anomeric effect or the antiperiplanar lone-pair hypothesis. While it is quite erroneous to label this hypothesis as the stereoelectronic effect , the fact that this situation has come about does serve to emphasize the ascendency of this hypothesis in the minds of many organic chemists. 

On the foundation of these theoretical studies, Gorenstein builds a series of postulates of far-reaching consequence for the kinetic anomeric effect and mechanistic phosphorus chemistry in general. It is important to review the noninterpretational data derived from these theoretical calculations. 

Addition of triphenylphosphine-deuterobromide to tri-O-acetyl-D-glucal followed by addition of deuteroethanol afforded 5 as the main product (a 3 ratio was 3 1 and equatorial axial deuteron ratio was 2 1). The former ratio may result from the influence of the kinetic anomeric effect applying during the trapping of the intermediate oxonium ion 6. The results from this reaction and several other examples were used as evidence that the addition of alcohols to glycals under acid catalysis does not proceed by a trans diaxial process. ... 

If a true oxycarbenium ion is involved, one can expect that the stereoselectivity will be governed by the kinetic anomeric effect [6-8] leading to a predominant axial stereochemistry at C-1, the a/P ratio being of course modulated by steric effects (a 3-axial substituent can override the stereoelectronic effect). Oxycarbenium ions 2 and 3 lead to a-D-manno 6 and a-u-gluco 9 pyranosides respectively. Altogether, 2-deoxy-a-glycopyranosides can be predicted to be more easily attained after replacement of E by hydrogen. 

Franck [12] has shown that the major axial stereochemistry at the anomeric center is not due to a trans addition. No strong bridging of the proton can be really expected and the oxycarbenium ion 11 should be the reactive intermediate (Scheme 2). The use of deuterated alcohols ROD with catalytic amounts of Ph3P HBr showed that deuteron delivery occurs largely from below the plane of the double bond. The predominant axial stereochemistry at C-1 and C-1 of the glycoside products 12 and 15 probably arises from the kinetic anomeric effect. 

These results are consistent with an Ad 2 (addition-electrophilic-bimolecular) mechanism for a first step of protonation, followed by a glycosyl transfer usually directed by the kinetic anomeric effect. Theoretical calculations [13] have shown... 

It is assumed that this kind of interaction causes a phenomenon known as the kinetic anomeric effect, which sta-bUizes the transition state for the bond forming at the Cl position, where the axial attack of the incoming nucleophile on the Cl position is favored (Scheme 38.1). 

The syn- versus anti- displacements and the stereoselectivity of the 5 1 reactions (5 2 reactions with an internal nucleophile), which are widely used for making three- to seven-membered cyclic compounds, " and a critical discussion of the factors affecting the chemical glycosylation reaction, which concludes that the kinetic anomeric effect is not responsible for the selectivity in these reactions, have been reviewed. 

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