Aldoses aldonolactone reduction

Isotopic Labeling and Substitution at the Anomeric Center of Aldoses by Reduction of Aldonolactones... 

VIII. Reduction of Aldonolactones 1. Reduction to Aldoses and Alditols... 

N. Sperber, H. E. Zaugg, and W. M. Sandstrom, The controlled sodium amalgam reduction of aldonolactones and their esters to aldoses and an improved synthesis of D-arabinose, J. Am. Chem. Soc., 69 (1947) 915-920 and references cited therein. 

There is no generally useful nonhydride method for the direct reduction of carboxylic acid esters to aldehydes. There are, however, procedures which are valuable under particular circumstances. An important example is the one-electron reduction of aldonolactones to aldoses. Two factors presumably contribute to the success of these reactions firstly the presence of electron-withdrawing substituents in the substrates, raising the reactivity of the carbonyl group, and secondly the ability of the products to form cyclic hemiacetals stable to further reduction. 

The use of sodium amalgam originates with E. Fischer. The method was a cornerstone of his aldose homologation (cyanohydrin formation, hydrolysis, lactone formation and reduction) which was so important to the development of carbohydrate chemistry. Although the yields obtained by Fischer were moderate ca. 20-50%), more recent work by Sperber et al. has resulted in significant improvements. In particular, they discovered that control of the pH of the reaction mixture was very important. At pH 3-3.5, yields in the range 52-82% were obtained with a variety of aldonolactones. As an example, the preparation of arabinose is shown in equation (4). If the pH was allowed to rise, yields were lower due to overreduction. Methyl esters of aldonic acids could also be used as substrates. 

Early work showed that the reduction of aldonolactones to aldoses may also be carried out by catalytic hydrogenation over Pt02 in aqueous solution.4 Using this method, o-glucono-1,5-lactone was reduced to glucose in up to 80% yield, the remainder of the product being o-gluconic acid. However, careful optimi-... 

In this chapter, methods for oxidation, reduction, and deoxygenation of carbohydrates are presented. In most cases, the reactions have been used on aldoses and their derivatives including glycosides, uronic acids, glycals, and other unsaturated monosaccharides. A number of reactions have also been applied to aldonolactones. The methods include both chemical and enzymatic procedures and some of these can be applied for regioselective transformation of unprotected or partially protected carbohydrates. 

Unprotected aldoses and ketoses can be reduced to afford alditols while aldonolactones can be reduced to give either aldoses or alditols. The reagent of choice for reduction to alditols is sodium borohydride since it is both cheap and convenient to use. The reduction is carried out under mild conditions at room temperature in an aqueous solution. Sodium borohydride is stable in water at pH 14 while it reacts with the solvent at neutral or slightly acidic pH, but at a slower rate than the rate of carbonyl reduction. In some cases, the product will form esters with the generated boric acid. These borate complexes can be decomposed by treatment with hydrochloric acid or a strongly acidic ion-exchange resin and the boric acid can be removed in the work-up as the low boiling trimethyl borate by repeated co-evaporation with methanol at acidic pH [155]. 

The reduction of aldoses/ketoses occurs readily with sodium borohydride and during the reaction the pH increases to about 9 (O Scheme 19) [155]. For the reduction of aldonolactones in water the first step of the reduction has to be carried out at a pH around 5 in order to avoid ring-opening of the lactone to the corresponding sodium salt which will not react with sodium borohydride. The pH control can be achieved by performing the reduction in the presence of an acidic ion-exchange resin, e. g., Amberlite IR-120 [156]. In this way, it is possible to stop the reduction at the aldose step. Alternatively, more sodium borohydride can be added and thereby increasing the pH to 9 by which the alditol is obtained (O Scheme 19). The reduction of aldonolactones to alditols can also be performed in anhydrous methanol or ethanol where hydrolysis of the lactone is not a side reaction [156]. 

The non-catalytic reduction of aldonolactones to the corresponding aldoses and/ or alditols by sodium borohydride or lithium aluminum hydride has also been studied [1]. Because of the stoichiometric character of these procedures they are, however, limited to laboratory use. 

When the bromodeoxy lactones were boiled in water tetrahydrofurans were formed, whereas catalytic hydrogenation caused deoxygenation at C-2 and/or at the primary position, while the acetylated aldonolactones could also be reduced to 3-deoxylactones after elimination and stereospecific reduction. Substitution by azide introduced nitrogen functions at C-2 or at both bromo-substituted carbons, and these compounds could be converted into the corresponding amino acids. The new molecules could furthermore be reduced to the corresponding aldoses or alditols. 

Two new methods for the reduction of aldonolactones to aldoses have been developed for use in small-scale syntheses either the lactone itself was reduced with diborane in THF, or an 0-tetrahydropyranyl derivative was reduced with a 1 1 mixture of lithium aluminium hydride and aluminium chloride in ether. The yield of aldose depends on a number of factors and may be low due to the ease of reduction of the aldose to the alditol. The catalytic hydrogenation of D-glucose in the temperature range 100—170 °C and at pressures of 20—80 atmospheres has been examined the effects of pH and promoters (e.g. magnesium, barium chloride, calcium sulphate) were also examined. The rate of hydrogenation was enhanced at pH 8, and calcium sulphate was the most effective promoter at pH 6.8. 

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