Nucleophilic substitutions glycosylations

Figure 25.7 Glycoprotein formation occurs by initial phosphorylation of the starting carbohydrate to a glycosyl phosphate, followed by reaction with UTP to form a glycosyl uridine 5 -diphosphate. Nucleophilic substitution by an -OH (or -NH2) group on a protein then gives the glycoprotein.

Anomeric halides follow the typical reactivity order F < Cl < Br < I for nucleophilic substitutions. They have been used in stereoselective O-glycosylation, nucleophilic displacement, and carbanion as well as in radical reactions. 

Carboxylates are stable to anhydrous hydrogen fluoride,30 but as described above, how ever, hemiacetal esters are readily cleaved and fluorinated by anhydrous hydrogen fluoride or 70% hydrogen fluoride/pyridine, this method has been widely applied in the synthesis of glycosyl fluorides from glycosyl esters for reviews see refs 29, 34, 277-279. 288, 289. Furthermore, p-toluene- or methanesulfonates (but not trifluoroacetates) of primary alcohols arc fluorinated by nucleophilic substitution using tctrabutylammonium hydrogen fluoride. This procedure is less suitable for secondary alcohols because of the considerable number of elimination products 306 for example, formation of 1 compared to 2.306... 

The chymotiypsin reaction is one example of acyl group transfer (see Fig. 6-21). Glycosyl group transfers involve nucleophilic substitution at C-l of a sugar ring, which is the central atom of an acetal. In principle, the substitution could proceed by an SnI or Sn2 path, as described for the enzyme lysozyme (see Fig. 6-25). 

In his last years, Dr. Isbell became convinced of the importance of saccharide peroxides as reaction products, and not merely as intermediates. He pointed to the structural similarity that exists between hydrazines, hydroxylamines, and peroxides and suggested that a missing group, saccharide peroxides, might be prepared by nucleophilic substitution using suitably protected glycosyl halides and aryl peroxides, as shown in the scheme below. 

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... 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

Syntheses from precursors of types (405) and (406) are rare, and of type (407) are unknown. One example of the first of these is the oxidative cyclization of pyrimidine (408) to the glycosyl pyrimidotriazine (409) (Equation (68)) <82MI 720-01). An interesting example of the second type is the cyclization of the 6-chloropyrimidine (411). In the presence of air this affords 2-methyl-fervenulone (412) by straightforward intramolecular nucleophilic substitution of the chlorine atom. Pyrolytic cyclization of compound (411), however, affords the isomeric 1-methyl product (413), possibly via a diaziridine intermediate (Scheme 33) <75JOC232i>. 

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. 

A thiophilic electrophile (+SMe) from DMTST reacts with a lone parr on sulfur to afford a cationic sulfonium species, which is an excellent leaving group. Because of the participation of a lone pair on the ring oxygen, the C-S bond is cleaved, forming an oxocarbenium ion intermediate, with which MeCN reacts to form an axial-oriented nitrilium intermediate under kinetic control. This then undergoes Sn2 nucleophilic substitution with a hydroxyl of the glycosyl accepter to yield a-sialoside. 

Transferases catalyze the transfer of functional groups such as methyl, hydroxymethyl, formal, glycosyl, acyl, alkyl, phosphate, and sulfate groups by means of a nucleophilic substitution reaction. They are not widely used in industrial processes however, there are a few examples of industrial processes that utilize transferases. 

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