Carbohydrates nucleophilic addition reactions

Y. Ali and W. A. Szarek, Synthetic approaches to gem-di-C-alkyl derivatives of carbohydrates Nucleophilic addition reactions of 3-C-methylene compounds derived from l,2 5,6-di-0-isopropylidene-ot-D-rifto-hexofuranos-3-ulose using phase transfer catalysis, Carbohydr. Res. 67 Cll (1978). 

Acetal and hemiacetal groups are particularly common in carbohydrate chemistry. Glucose, for instance, is a polyhydroxy aldehyde that undergoes an internal nucleophilic addition reaction and exists primarily as a cyclic hemiacetal. 

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides. 

Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, P amino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

The carbon that lost a proton is now a nucleophilic center and can therefore react with formaldehyde. As mentioned above, formaldehyde has an electrophilic center on carbon. Therefore, the carbon of formaldehyde can react with the nucleophilic carbon on the enolate of glycolaldehyde to form a new compound containing three carbon atoms, a three-carbon carbohydrate called glyceraldehyde. The overall reaction sequence is often called an aldol addition reaction, here of formaldehyde and glycolaldehyde. 

The stereochemical outcome of the addition of carbanions to ketones yielding tertiary alcohols (or secondary alcohols in the case of aldehydes) is variable and depends on the substrate, the counterion and the solvent. Numerous applications of this strategy to natural product synthesis from carbohydrates can be found in the literature and this approach was fruitful in pioneering syntheses of polyketide-type products. Here again, the template effect of the sugar plays a tremendous role in the stereochemical outcome of the reaction. Chelation controlled nucleophilic addition can also be used to form chiral centers in a highly predictable way. 

As alternatives to nucleophilic additions to C6 or C5 aldehydes, olefinations of the same compounds offer a repertoire of solutions to chain extensions or to the coupling of two carbohydrate building blocks. As shown in the above section, chain extensions at C6 are often followed by the introduction of new functional groups and thus new chiral centers. In this regard, olefins obtained via Wittig-type reactions are excellent starting compounds. 

Unlike the carbohydrates with double bonds at positions other than between C-1 and C-2 ( isolated alkenes ), which exhibit normal alkene chemistry, glycals are vinyl ethers and therefore undergo a number of highly selective addition reactions due to the strongly polarized double bonds and the presence of bulky substituents at the C-3 allylic centers. Straightforward addition reaction includes initial electrophilic addition at the double bond, followed by the addition of a nucleophile at C-1 to give the 1,2-trans adduct (O Scheme 19). 

Aldehydes and ketones react with alcohols by acid-initiated nucleophilic addition to form hemiacetals which are usually unstable. Reaction with a second mole of alcohol produces a acetal. Carbohydrates usually exist in hemiacetal or acetal forms. 

The common types of chemical reactions found in living cells are nucleophilic substitution, elimination reactions, addition reactions, isomerization reactions, and oxidadon-reduction reacdons. 21. In addition to being an important energy source, carbohydrates are important structural molecules in organisms and have a role in intracellular and intercellular communication. 

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