Nucleophilic substitutions anomeric carbon

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. 

A phosphite forms the phosphonium salt by interaction with a Lewis acid owing to their basic character. When a glycosyl phosphite is transformed to the phosphonium salt, the resulting phosphonooxy group acts as a strong leaving group in a nucleophilic substitution at the anomeric carbon. Since the early reports on their use... 

SCHEME 4.1 Glycoside synthesis by nucleophilic substitution at the anomeric carbon. 

In a different approach to the preparation of glycosides, the nucleophilic substitution takes place at the carbon atom of the aglycone rather than at the anomeric carbon (Scheme 4.53). In contrast to the methods discussed in Section 4.3, there is no scission of the glycosyl-oxygen bond in these reactions. Instead, the R-X bond is cleaved. 

The substitution reactions at the anomeric carbon usually proceed easily and via a SnI mechanism in most cases. However, it is not the case in the nucleophilic substitutions at nonanomeric sites. Because of the presence of vicinal electron-withdrawing substituents (OR or NHR) which strongly destabilize the intermediate carbocations, Sn2 displacement reactions instead of Sn 1 reactions are favored (O Scheme 1). 

Theoretical studies of tetrahedral carbon species have played an important role in the formulation of ALPH and the anomeric effect. Similarly, molecular-orbital calculations have been the touchpaper for development of the stereoelectronic effect in phosphorus chemistry. Early theoretical calculations indicated the influence of the anomeric and gauche effects in phosphates (Newton, 1973). But without doubt, the foray of Lehn and Wipff (1975) into this field provided the inceptive piece of research that was the impetus for a series of studies resulting in the proposition of a stereoelectronic theory with a far-reaching impact on nucleophilic substitution reactions at phosphorus. 

L. Pearce, Approach to oxetane and furan nucleosides with an anomeric carbon substituent Nucleophilic substitution at highly hindered a-bromo-oxetane- and -tetrahydrofuran-carboxy-lates. Tetrahedron Lett., 32 (1991) 3569-3572. 

So, the process shown in Figure 11.9 that leads to sucrose need not actually occur by a nucleophilic substitution reaction at the anomeric carbon. Indeed, the derivative of galactose (shown as guanosine diphosphate [GDP]) may be the uridine diphosphate (UDP) or ADP instead, and, of course, the displacement is enzyme mediated. 

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