Saccharinic acids 3-deoxy

Saccharinic acids are specific reaction products of monosaccharides in strong alkalies, particularly of alkaline-earth metals. They are obtained in each case as diastereomeric pairs by benzilic acid rearrangements from deoxy-hexodiuloses according to Formula 4.48a. In fact, l-deoxy-2,3-hexodiulose yields saccharinic acid, 3-deoxy-I,2-hexodiulose yields metasac-charinic acid and 4-deoxy-2,3-hexodiulose yields isosaccharinic acid (Formula 4.48b). 

The reducing-end units (see Fig. 8) are highly labile in alkaline solutions. After an initial attack by hydroxide ions at the hemiacetal function, C-1, a series of enoHzations and rearrangements leads to deoxy acids, ie, saccharinic acids, and fragmentation. Substituents on one or more hydroxyl groups influence the direction, rate, and products of reaction. 

Saccharinic acid formation has been studied for several years. The four-step reaction proceeds rapidly in alkaline solution because of basic catalysis, particularly in the last two steps. Initially formed is an enediol that can undergo j8-elimination of a functional group, usually a hydroxyl group. The final two steps involve tautomerization to an a,j8-dicarbonyl intermediate followed by a benzilic acid rearrangement. This sequence is shown in Scheme 6 for the formation of the a- and j8 -xylometasac-charinic acids (30) by way of 3-deoxy-D-g/ycero-pentos-2-ulose (29). 

In alkaline solutions D-glucose forms 3-deoxy-D-en/f/iro-hexosulose and 4-deoxy-D-gft/cero-2,3-hexodiulose which yield saccharinic acids. Machell and Richards (57) have shown that 3-deoxy-D-en/fhro-hexosulose (14) is oxidized by 30% hydrogen peroxide to formic acid and 2-deoxy-D-erythro-pentonic acid (15). Recently Rowell and Green (58) found that 14 in the presence of oxygen also forms 15 in addition to the saccharinic acids. They inferred that the reactions with oxygen and hydrogen peroxide are very similar, but they did not present reaction mechanisms. 

This section deals with acids, that are formally modified aldonic acids, such as keto, deoxy, and branched-chain acids (including the so-called saccharinic acids). The aminoaldonic acids, which are oxidation products of amino sugars, and, in particular, the important nonulosaminic acids (neuraminic acids) and muramic acid, are not discussed here. The formation of saccharinic acids by the treatment of sugars with alkali, and the mechanisms involved, are likewise outside the scope of this chapter. 

Ishizu et al.29H found that D-xylose and D-fructose react with aqueous calcium hydroxide to produce 13 lactonizable saccharinic and other acids. These were identified after separation by cellulose column and gas-liquid chromatography, and the Cs-saccharinic acids, 2-C-methyl-D-threonic acid (117) and 2-C-methyl-D-erythronic acid (118), were among those isolated. These authors299 later reported that L-sorbose reacts similarly, to generate 14 lactones, including the 2-C-methyl-L-xr/o o-l,4-lactone and 2-C-methyl-L-lyxono-1,4-lactone, which were also prepared from 1-deoxy-L-threo-pentulose via the cyanohydrin reaction. 

Three structurally isomeric forms have been established for the six-carbon saccharinic acids. In the order of their discovery, these are the sac-charinic or 2-C -methylpentonic acids, the isosaccharinic or 3-deoxy-2-C -(hydroxymethyl)-pentonic acids, and the metasaccharinic or 3-deoxy-hexonic acids. Although none of these six-carbon, deoxyaldonic acids has been crystallized, six are known in the form of crystalline lactones (saccharins). All the possible metasaccharinic acids of less than six-carbon content have been obtained, in the form of crystalline derivatives, by the sugar-alkali reaction. Only one example of a branched-chain deoxyaldonic acid (the racemic, five-carbon isosaccharinic acid) of other than six-carbon content has been so obtained. The formation of saccharinic acids containing more than six carbon atoms remains to be explored. 

Deoxy-D-l2/a o-hexonic acid ( /3 -D-galactometasaccharinic acid) was discovered by Kiliani and Sanda as a minor product of the n-galactose-al-kali reaction. Kiliani believed that this product was a new type of branched-chain saccharinic acid, and referred to it throughout subsequent publications as parasaccharinic acid. The evidence, provided both by his own work and that of Nef, that Kiliani s parasaccharinic acid contained, in fact, the epimer of a -D-galactometasaccharinic acid, is outlined on page 56. 

Although Nef had prepared the dl form of this saccharinic acid and had converted it to 2-deoxy-j)h-glycero-tetr vic acid (nL-malic acid), Glattfeld and Miller succeeded in separating the dl compound into its enantio-morphous forms and thus established the absolute configuration of the optical isomers. 

VIII) which yielded, on treatment with sodium in ether, 1,2-anhydro-DL-glyceritol (glycidol XVI). Reaction of the latter with hydrogen cyanide produced 2-deoxy-DL-ffZi/cero-tetrononitrile (IX). Hydrolysis of the nitrile (IX) with barium hydroxide afforded the desired saccharinic acid (lab). 

Dihydroxybutanoic acid, a 3-deoxytetronic acid, is the only theoretically possible four-carbon metasaccharinic acid it was isolated by Nef in the dl form (Ilab) in the course of his work on the action of sodium hydroxide on D-arabinose. It therefore constitutes the only four-carbon saccharinic acid isolated to date from a sugar-alkali reaction. Resolution of this on acid (Ilab) was accomplished by Nef, who showed that the dextrorotatory acid (Ila) upon oxidation gave rise to 2-deoxy-L-f/Z2/cero-tetraric acid [(-)-)-d-malic acid XV]. During the course of this work, several derivatives of the L and DL saccharinic acids (lib and Ilab) were prepared, but only the brucine salt of the d acid (Ila) was reported. 

A review (in Russian) has been published by Gakhokidze, and the same author has reported on the conversion of 3,4,6-tri-O-acetyl-D-mannose into 2-deoxy-D-araZ>mo-hexonic acid(orthosaccharinic acid) by use of aqueous lead hydroxide. The first naturally occurring branched-chain saccharinic acid, 2-C-methyl-D-erythronolactone, has been isolated from milk vetch Astragalus lusitanicus) Reduction of the isosaccharinic acids (13) and (14) with sodium borohydride gave mixtures of the corresponding free sugars and branched-chain alditols. ... 

A 3-deoxy-2-ketogluconic acid 6-phosphate was isolated as an intermediate in the enzymic oxidation of gluconic acid 6-phosphate 135a). The formation of this acid by a dehydration mechanism is reminiscent of that of the saccharinic acids. 

It is of interest that, in 1882, lime-water treatment of lactose was found to yield the insoluble calcium a -D-isosaccharinate, a rearrangement product of the n-glucose component, and, in 1896 and 1899, Lobry de Bruyn and Alberda van Ekenstein" observed that treatment of lactose with either lead hydroxide or potassium hydroxide liberated n-galactose. Kiliani established the structure of the saccharinate as that of a 3-deoxy-2-C-(hydroxymethyl)pentonic acid and, had the mechanism of its formation been understood (see p. 188), this would have been sufficient evidence... 

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