Nucleophilic substitutions anomeric configuration

Acetonitrile is another participating solvent, which in many cases leads to the formation of an equatorially linked glycoside [125-131], It has been proposed that these reactions proceed via an a-nitrilium ion intermediate. It is not well understood why the nitrilium ion adopts an axial orientation however, spectroscopic studies support the proposed anomeric configuration [130,131], It is known that nucleophilic substitution of the a-nitrilium ion by an alcohol leads to P-glycosidic bonds and the best P-selectivities are obtained when reactive alcohols at low reaction temperatures are employed. Unfortunately, mannosides give poor anomeric selec-tivities under these conditions. 

In conclusion, it appears that conformational factors play the most important role in nucleophilic substitution with fluorine at C 2 of the sugar moiety but are not necessarify crucial in a similar nucleophilic displacement at C 3. It was reported that nucleophilic displacement of the 3 -hydroxyl group in 9-(2-deojgr-6-D-xylofuranosyI)adenine with DAST was completed Avithin 1 hour, whereas the same reaction with the 2 -hydroxy group of 9-(3-deoxy-6-D-arabinofuranosyl)adenine required 14 hours. This reflects an unfavorable electronic factors at C 2 due to the proximity of the anomeric center. Also, steric factors are in favor of the S 2 conversion of nucleoside 87 with DAST, since nucleophilic attack fi-om the a-side of the nucleoside is much more efficient than that from the B-side. Therefore, even unfavorable C 3 -endo conformation of 87 did not cause elimination and 3 -a-fluoro substituted derivative 90 was obtained in good yield. In contrast, displacement of the 2 -hydroxyl group in the ribo configuration, such as conversion of 25 to 27,31 to 35, or 41 to 42, is much more difficult, which requires the favorable C 2 -endo conformation in order to prevent undesired elimination. 

The experimental evidence obtained for the azide nucleophilic substitution in fluorides 3 and 5 suggests that the reaction follows a different mechanism in each case. a-Glucopyranosyl fluoride 3 yields die substitution product 4 with inversion of the configuration at the anomeric carbon, which is die expected result for a Sn2-type reaction (Scheme 13.5). 

If aspartic acid-52 acts as a nucleophile in lysozyme reactions a glycosyl enzyme intermediate will be formed [60]. There is no evidence, kinetic or otherwise, for substituted enzyme intermediates, but rapid breakdown might preclude attainment of detectable concentrations. Formation of a substituted enzyme could explain the observed retention of configuration at the anomeric carbon in transglycosidation reactions, provided backside attack in a subsequent reaction is chemically reasonable. It has therefore been important to attempt to understand the chemistry of acylal hydrolysis so as to assess the properties that would be expected of an acylal intermediate in reactions catalysed by the enzyme. 

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