Formation of Saccharinic Acids

Mechanism of Formation op Saccharinic Acids 1. The Fragment-recombination Mechanism of Kiliani and Windaus 

1 CHjOH CHjOH D -Glucosaccharinic acid 1 CH2OH CH2OH D-Isosaccharinic acid 

This idea was expanded by Windaus, who suggested that not only 

D-glucosaccharinic acid but also D-isosaccharinic acid and Kiliani s para-saccharinic acid might be formed by recondensation of appropriate alde-hydic fragmentation products with a lower-carbon metasaccharinic acid. He proposed that the unbranched metasaccharinic acids, in contrast, are formed by direct dismutation of the isomeric sugars. 

Nef s theory of the mechanism of formation of the saccharinic acids is outlined, in its original form, in a paper published in 1907 and, in its final form, in his comprehensive article of 1910. The theory proposes that the reaction takes place in two major steps (a) the isomerization of the sugar, with loss of water, to an a-dicarbonyl compound, and (b) a benzilic acid type of rearrangement of the latter, with hydration, to the saccharinic acid. The second step involves chain rearrangement in the production of the saccharinic, isosaccharinic, and Kiliani s parasaccharinic acids, but not in the production of the metasaccharinic acids. 

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Because a benzilic acid rearrangement is the last step in the formation of saccharinic acids the difference between these results could be due to complexation of hydroxyl groups and alkoxide anions by the divalent calcium ions. Such a complexation apparently promotes isomerization and, hence, a fragmentation-recombination to the xylosaccharinic acid. This route has been questioned, and yet it provides a rational explanation of the results. 

This benzilic acid type of rearrangement is the result of the action of alkali on the dicarbonyl compound, and is accelerated by calcium ions. The formation of saccharinic acids by the action of aqueous alkali on sugars is very well known 82,84,92 however, if ammonia is present, very little8 or no production of saccharinic acid has been reported. The reaction of the intermediate carbonyl compounds with ammonia is faster than the benzilic acid type of rearrangement to give saccharinic acid, and, hence, substituted imidazoles are formed, as illustrated in Scheme 9. 

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. 

However, Head showed that glyoxal is produced by the treatment of both oxycellulose and periodate-oxidized methyl fl-cellobioside (121) with alkali. The other theory was that of Haskins and Hogshead, based on the p-alkoxycarbonyl elimination mechanism of Isbell for the formation of saccharinic acids on treatment of sugars with alkali. They suggested that fission of the C5—O bond would yield glyoxal and n-erythrose. Recent work has indicated that the degradation is, indeed, based on a jS-alkoxycarbonyl elimination, but the products are different from those postulated above. 

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. 

This work on the isomerization of D-glucose was responsible for the intensive interest which Sowden developed in saccharinic acids. From Schaffer s work, Sowden learned of the relative ease of isolation of saccharinic acids from isoraerized solutions. As a result, Miss Dorothy J. Kuenne was started on an investigation of the mechanism of formation of saccharinic acids, and the first report of this work was published in 1953. In the next few years, six additional investigations were reported in which specially labeled sugars played an important role. To Volume 12 of this Series, Sowden contributed a review on saccharinic acids which presents a clear and impressive account of the state of this complex area of sugar chemistry. 

HMPT at room temperature to give the 3, 4 -unsaturated nucleoside. Details of the formation of saccharinic acid nucleosides from 2, 3 -diketo-nucleosides have appeared (c/. Vol. 8, p. 151). 

Fiqure 4.48 Formation of saccharinic acids from glucose and fructose. 

Dilute alkali may also cause degradation of reducing sugars and the enolisation may extend to the 2,3-dienol together with the production of such breakdown products as glyceraldehyde. Rearrangements can also take place with concentrated alkali with the formation of saccharinic acids. D-Glucose (CLI) yields saccharinic acid (CL) with dilute alkali and a mixture of iso- (CLII) and wcte-saccharinic acid (CLIII) with more concentrated alkali. 

In the formation of C6 acids (namely, organic acids containing 6 or fewer carbon atoms), at OH concentrations greater than 10 mM, route 5 occurs preferentially to route 6, and lactic acid and saccharinic acids predominate in the product,... 

G. Machell and G. N. Richards, Mechanism of saccharinic acid formation. Part II. The a, /3-dicarbonyl intermediate in formation of D-glucoisosaccharinic acid, J. Chem. Soc., (1960) 1932-1944. 

The best evidence for the formation of 8 -D-isosaccharinic acid in the sugar-alkali reaction is the recent observation" that treatment of lactose, maltose, or 4-0-methyl-D-glucose with lime-water at room temperature provides initially a mixture of saccharinic acids consisting almost exclusively of a -D-isosaccharinic acid plus an acid with the properties of Nef s /3 -D-isosaccharinic acid [brucine salt, m. p. 185 to 210 (dec.), [a]n - 20 to —22° lactone, [ajp -)-6 to - -8.5°]. An experimental proof that this substance possesses the isosaccharinic acid structure would provide the necessary evidence that it is, indeed, the epimer of a -D-isosaccharinic acid. 

The successive isomerization of an aldose to a 2-ketose and then to a 3-ketose was explained by assmning the intermediate formation of 1,2- and 2,3-enediols. Thus, a single aldose, under the influence of alkali, could produce all three types of saccharinic acid. 

The general statement of the isomerization mechanism, as given in the opening paragraph of this Section, is accepted at the present time as a mechanism of saccharinic acid formation. However, Nef s concept of the mode of isomerization of the original sugar to the intermediate a-dicarbonyl compound has undergone radical revision. 

The final phase of the Nef mechanism, which involves a benzilic acid type of rearrangement of a-dicarbonyl intermediates to the saccharinic acids, is at present accepted as a feature of saccharinic acid formation. Nef s concept of the conversion of reducing sugars to the a-dicarbonyl structures required revision, however, when it became evident that the formation, in this step, of the proposed methylenic intermediates is highly improbable. A departure from the methylenic intermediates was suggested in 1926 by Evans and Benoy, who proposed that the a-dicarbonyl intermediates of the Nef mechanism might arise by successive dehydration and rehydration from the enediols. It is now recognized, however, that forma-... 

The Isbell ionic mechanism for the formation of the various types of saccharinic acid, as well as for Nicolet s conversion of 2-hydroxy-3-methoxy-3-phenylpropiophenone to 2,3-diphenyllactic acid, involves the following successive steps (1) the formation and ionization of an enediol (2) the /3-elimination of a hydroxyl or an alkoxyl group (3) rearrangement to an a-dicarbonyl intermediate and (4) a benzilic acid type of rearrangement to the saccharinic acid. 

The role of substitution in determining the course of saccharinic acid formation has been critically examined recently by Kenner and coworkers. They conclude that an 0-glycosyl or 0-alkyl anion is more readily extruded from the sugar enediol anion of the Isbell mechanism than is a hydroxyl ion. In addition, substitution at certain positions in the sugar molecule may inhibit competing side-reactions. For example, a substituent at C4 of the hexose molecule inhibits cleavage (by reverse aldolization) into two three-carbon fragments and the resultant formation of lactic acid, a result that had been demonstrated earlier by the experiments of Evans and his associates. A combination of the two above effects, then, preferentially... 

In contrast to the above formation of metasaccharinic acid, fragment recombination appears to be a predominant feature in the formation of the branched-chain a -D-glucosaccharinic acid from D-mannose-l-C plus lime-water. In this case, the radioactivity originally present in Cl of the hexose was found to have become distributed almost entirely between the methyl carbon atom and the tertiary carbon atom of the saccharinic acid, with the latter atom more heavily labeled than the former. In contrast to these observations, the Isbell mechanism, in the absence of compli-... 

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. 

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