Anomeric nucleophiles

The direct metallation of sugar derivatives, shown in Figure 7.20, is a useful method for the preparation of anomeric nucleophiles. Anomeric halides and glycals are excellent substrates for this reaction. Additionally, selective generation of a and 3 anomers is possible. 

S. Cao and R. Roy, Phase-transfer catalyzed anomeric nucleophilic substitutions occur by an SN2-type mechanism, Carbohydr. Lett., 2 (1996) 27-34. 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

Ar-Acyl oxy- A -a 1 k oxyamides have been found to undergo SN2 reactions with a number of organic and inorganic nucleophiles including anilines, thiols, hydroxide and azide anions. Reaction products from all of these processes are themselves reactive anomeric amides and outcomes have uncovered novel chemistry of this unusual class of compounds. 

The Tsuji-Trost reaction is the palladium-catalyzed allylation of nucleophiles [110-113]. In an application to the formation of an A-glycosidic bond, the reaction of 2,3-unsaturated hexopyranoside 97 and imidazole afforded A-glycopyranoside 99 regiospecifically at the anomeric center with retention of configuration [114], Therefore, the oxidative addition of allylic substrate 97 to Pd(0) forms the rc-allyl complex 98 with inversion of configuration, then nucleophilic attack by imidazole proceeds with a second inversion of configuration to give 99. 

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. 

A useful extension of the in situ anomerization process involves the employment of C-nucleophiles such as vinyl and allyl magnesium bromides. Grignard reactions to per-O-benzylated glycosyl iodides proceed stereoselectively when a strong nucleophile like allyl magnesium bromide is used, giving [1-C-allyl fucosides (95% P-only)... 

The reaction of phosphines and alkyl halides presents an alternative way to generate phosphonium electrophiles (Scheme 3.8). In particular, the combination of a phosphine and carbon tetrabromide (the Appel reaction) allows for in situ formation of a phosphonium dibromide salt (48, X = Br). Treatment of a hemiacetal donor 1 with the phosphonium halide 48 initially provides the oxophosphonium intermediate 38 (X = Br). However, the oxophosphonium intermediate 38 can react with bromide ion to form the anomeric bromide intermediate 49 (X = Br) with concomitant generation of phosphine oxide. With the aid of bromide ion catalysis (i.e. reversible, catalytic formation of the more reactive P-anomeric bromide 50) [98], the nucleophile displaces the anomeric bromide to form the desired glycoside product 3. The hydrobromic add by-product is typically buffered by the presence of tetramethyl urea (TMU). 

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