Alkylation reactions carbohydrate derivatives

Similarly, carbohydrates often exist in an equilibrium between a cyclic h niacetal form and a carbonyl form with the latter in an extremely low quantity (14). Therefore, for alkylation of carbohydrate derivatives in organic solvent, extensive functional group transformation and derivatization is required to generate the desired carbonyl. However, in the aqueous reaction, the hemiacetal-form and the carbonyl form is in a constant equilibrium. And the carbonyl form will react, which drives the equilibrium until all the starting material has reacted (eq. 7). 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Alkyl (or acyl) derivatives of the 6-amino-6-deoxy carbohydrates are examples of derivatives in which the hydrophilic and hydrophobic moieties are linked at other positions than C-1. Thus 6-amino-6-deoxy-D-galactose derivatives 34 were prepared from l,2 3,4-di-0-isopropylidene-6-0-tosyl-a-D-galacto-pyranose by the following reactions (1) substitution of the leaving group at C-6 by a phthaloyl function, (2) hydrazinolysis to afford a 6-amino-6-deoxy intermediate, (3) reaction of acyl or sulfonyl chlorides at the amino function, (4) deprotection of the acetal rings to afford the expected glycolipid 34 [56]. 

The action of thiophosgene on carbohydrates in the presence of base and the reaction of a sodium-carbohydrate with a suitable 0-[(alkyl-thio)thiocarbonyl] derivative both give rise to intermolecular thionocarbonates. 

In a stereocontrolled route to thromboxane B2, Corey and coworkers used the Eschenmoser rearrangement for the preparation of lactone (91 Scheme 14). The product of the 3,3-sigmatropic shift, amide (90), is directly iodolactonized, thus avoiding often troublesome amide hydrolysis conditions. Another application involving a carbohydrate derivative was demonstrated by Fraser-Reid and coworkers (Scheme 15). Reductive elimination of benzylidene (92), followed by in situ alkylation, Wittig reaction, DIBAL-H reduction and rearrangement, led to amide (94), which was transformed into the corresponding pyranoside diquinane by double radical cyclization. 

Alkylation requires more vigorous conditions. These reactions were originally performed on the stannylene acetal with the alkylating reagent in DMF at elevated temperatures, 45 °C for methyl iodide or 100 °C for benzyl bromide. It was then discovered that the presence of added nucleophiles markedly accelerates the reactions so that alkylation of dibutylstannylene acetals in benzene, which were very slow at reflux with benzyl bromide alone, occur at a reasonable speed at reflux in the presence of added tetra-butylammonium halides. Many other nucleophiles are also effective, including A-methylimidazole and cesium fluoride. Cesium fluoride has been used mainly in DMF and the combination of an added nucleophile with a polar aprotic solvent allows benzylation with benzyl bromide to occur efficiently at room temperature. If the stannylene acetal is a 1,2-D-stannylene acetal derivative of a carbohydrate and the electrophile is a carbohydrate-derived triflate, oligosaccharide synthesis can be achieved. More recently, both formation of the stannylene acetal and alkylation in the presence of tetrabutylammonium iodide have been performed under microwave irradiation excellent yields have been obtained in <0.5 h and the short reaction times allow the use of more sensitive reagents (Scheme 5.1.10). ... 

Chantal et al. (8,10) have studied the effect of methanol cofeeding on product distribution from phenolic compounds. They proposed an oxonium mechanism to explain alkylation where oxonium ions are generated from diphenylether and anisole, intermediates that were formed from phenolic starting materials. They used low levels of methanol in these experiments 90/10 (phenol/methanol) vs 1/1 (wood pyrolzate/methanol) in the results reported in this paper and by Chen et al. (12). Under conditions of high methanol concentrations, and in the presence of carbohydrate-derived material, the formation of an oxonium ion from methanol (CH30H2 ) as proposed by Aranson et al. (24) is also possible. Direct reaction with either wood-derived reactants or various products from zeolite catalysis could explain the observed synergistis effect. 

Synthesis. - A report on perspectives on alkyl carbonates in organic synthesis has appeared. This contains applications of alkyl carbonate protecting groups in carbohydrate chemistry, carbonate exchange reactions and subsequent modifications as applied to carbohydrate derivatives and promotion of glycosylations. ... 

Other reactions of carbohydrates include those of alcohols, carboxylic acids, and their derivatives. Alkylation of carbohydrate hydroxyl groups leads to ethers. Acylation of their hydroxyl groups produces esters. Alkylation and acylation reactions are sometimes used to protect carbohydrate hydroxyl groups from reaction while a transformation occurs elsewhere. Hydrolysis reactions are involved in converting ester and lactone derivatives of carbohydrates back to their polyhydroxy form. Enolization of aldehydes and ketones leads to epimerization and interconversion of aldoses and ketoses. Addition reactions of aldehydes and ketones are useful, too, such as the addition of ammonia derivatives in osazone formation, and of cyanide in the Kiliani-Fischer synthesis. Hydrolysis of nitriles from the Kiliani-Fischer synthesis leads to carboxylic acids. 

Tetraalkylammonium salts have been used as phase transfer catalysts for alkylation [5], sulfonylation [46], and benzoylation reactions [47] of carbohydrate derivatives in mixed organic/aqueous solvent. For example, benzyhdene-protected methyl a-glucopyranoside underwent selective benzylation at the more acidic 2-OH group in the presence of a phase transfer catalyst (Scheme 11). 

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