Saccharinic acids derivatives

The saccharinic acids formed from hexoses have been especially examined because of the relationships of the a and /8 isomers (C-2 epi-mers). Structures of saccharinic acids derived from D-glucose are glu-cometasaccharinic acid (51), glucoisosaccharinic acid (52), and glucosaccharinic acid (53). The a- and /3- isomers of metasaccharinic acid can reversibly isomerize when exposed to base because of the labile proton at C-2. 

F. J. Lopez Aparicio, I. Izquierdo Cubero, and M. D. Portal Olea, Synthesis of saccharinic acid derivatives, Carbohydr. Res., 129 (1984) 99-109. 

Methyl groups attached to benzene rings can be reacted with oxygen to produce aromatic carboxylic acids. Benzoic acid, the parent aromatic acid, finds wide use as a food preservative and in metal corrosion inhibitors. Aspirin and saccharin are derivatives of benzoic acid. 

In the carbohydrate series, the acids encountered are aldonic, aldaric, uronic, or saccharinic acids. Often, these acids are readily transformed into their lactones or methyl esters, and it is as derivatives of these that they are commonly studied. Table VIII (see p. 136) records examples in which derivatives of such acids and lactones have been subjected to gas-liquid chromatography. 

The separation of saccharinic acids as their O-trimethylsilyl derivatives has also been used by Feather and Harris512 in a study on decomposition of sugars and in studies on bacterial polysaccharides.434... 

This mechanism is illustrated in Scheme 4. The reaction occurred in 0.2 M methanolic sodium hydroxide, and the isosaccharinic acid derivatives 78a and 78b obtained constitute the first saccharinic acid nucleosides reported. The configuration of the isomers at the branch-point was established by spectroscopic58 and chemical59 means. 

For the synthesis of A -Nps amino acid derivatives various Nps-donating reagents have been proposed (Scheme 46) (1) 2-nitrophenylsulfenyl chloride (Nps-Cl, 92),P5i-592,607] 2) 2-nitro-phenylsulfenyl thiocyanate (Nps-SCN, 95), (3) 4-nitrophenyl 2-nitrophenylsulfenate (Nps-ONp, 93), and (4) 2-(2-nitrophenylsulfanyl)-l,2-benzoisothiazole-3(2/i -one 1,1-dioxide (Nps-saccharin, 94). ... 

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. 

The melting points and optical rotations of saccharinic acids and their derivatives are recorded in Table I with the corresponding literature references. 

In the food industry, sulfur dioxide and sulfites are extensively employed as preservatives to inhibit microbial spoilage and increase the storage life of foods. In addition, several sulfamic acid derivatives like saccharin (13) (1878), cydamate (14) (1937) and acesulfame potassium (15) (1973) are important artificial sweeteners (Figure 4). 

Many organosulfur compounds have major industrial uses. For instance, carbon disulfide and DMSO are important commercial solvents and dithiocarbamates are used in the rubber industry as vulcanisation accelerators long chain alkanesulfonic or arenesulfonic acids are important synthetic detergents. Xanthates are used in the manufacture of rayon (see Chapter 8, p. 135) and cellophane, and many commercial dyes contain sulfonic acid groups (see Introduction, p. 5). Sulfamic acid derivatives such as saccharin (see Chapter 9, p. 162) acesulfame potassium (see Introduction, p. 5) and cydamates (see Chapter 9, p. 162) are valuable artificial sweeteners. 

The sulfur derivative (87) is 1000 times as sweet as sugar and without the bitter after-taste of saccharin however, it was discovered that N-alkylation of (87) removed the sweetness. On the other hand, in the saccharins (88a)-(88e) containing substituents in the 4-position and 6-position, sweetness was retained after N-alkylation. Many sulfamic acid derivatives are sweet, and there have been numerous studies of structure-taste relationships which have highlighted the importance of molecular shape and stereochemistry (see Chapter 9, p. 162). Two sulfamates which are commercial, non-nutritive sweeteners are cyclamate (85) and acesulfame potassium (86) (Figure 11). Cyclamate (85) is manufactured by refluixing cyclohexylamine either with triethylamine-sulfur trioxide in dichloromethane or with sulfamic acid (see Chapter 9, p. 162). 

M-Acetylsaccharinyl acid derivatives 408, which are structurally related to COX-2 inhibitor celecoxib, were designed and synthesised [133] from M-saccharinyl acetate 407a, prepared via the reaction of ethyl bromoacetate with sodium saccharin by heating the reactants in DMF (see [133]). Its transformation into the corresponding hydrazide 407b and subsequent reaction with ethyl acetoacetate, /3-diketones and maleic anhydride, afforded the heterocyclic compounds 408 [134] (Scheme 97). 

The formation of deoxyosones, such as, for example, the 3-deoxyosones, appears to be the most important of the dehydration reactions which may take place during Lobry de Bruyn-Alberda van Ekenstein transformations. This type of reaction, which NeP first proposed in suggesting mechanisms for saccharinic acid formation, is difficult to study because the products are seldom stable in the reaction mixtures in which they are formed. Nevertheless, several different lines of evidence now indicate that reducing sugars undergo primary dehydrations of this kind, and that deoxyosones do indeed mediate in saccharinic acid formation in basic solutions, as well as in production of 2-furaldehyde and its derivatives in acidic media. 

The reactions leading to the saccharinic acids and to 2-furaldehyde and its derivatives do not seem at this point to warrant further consideration as side reactions, since they have already been mentioned in connection with primary dehydration and related transformations. 

III. Tables of Properties of the Four-Carbon Saccharinic Acids and their Derivatives. 187... 

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 last attempt at synthesis was made by the preparation of 2-(hydroxy-methyl)glyceronic acid from 1,3-dihydroxy-2-propanone, but this product has not to date been transformed into the desired saccharinic acid (VI). Thus, this optically inactive acid has not been obtained in definitive form, nor have any of its derivatives been reported in the literature. 

It is fortunate that the ortho acid chloride is the major product in the chlorosulfonation because it is needed in the synthesis of saccharin, the first of the non-fattening sweeteners. The formation of the sulfonamide is like that of an ordinary amide, but the oxidation of the methyl group with potassium permanganate is probably new to you. It s a rather vigorous reaction, but one which very usefully turns toluene derivatives into benzoic acid derivatives. 

Syntheses of some pentonohydroxamic acid derivatives are covered in Chapter 10. Alkaline degradation of 5-O-a-D-glucopyranosyl-D-fructopyranose (leucrose) has afforded two novel saccharinic acids, 2-C-(2-hydroxyethyl)eiy-thronic acid and 2-C-(2-hydroxyethyl)threonic acid. Treatment of 4,6-O-ethyl-idene-D-glucose with the sulfur ylid JNr,iST-diethyl trimethylsulfonium-acetamide gave the epoxyaldonamide 6 as well as stereoisomers. ... 

Nitrones have been used with advantage as intermediates for the synthesis of N-hydroxyaminoacids . Amino groups of acid-sensitive compds., such as 0-ferf-butyl-protected amino acid derivatives, can be formylated with formic acid in the presence of dicyclohexylcarbodiimide . Peptides can be rapidly synthesized in aq. medium, without racemization, from a-amino acid N-carb-oxyanhydrides . Racemization of peptides can also be avoided by a new synthesis with saccharin . HF has been used for mild... 

The mechanism of the formation of the saccharinic acids and their derivatives remains unclear. Nef has suggested that the reaction proceeds through the diketone produced by removal of a molecule of water. This suggestion was combined by Isbell (68) with current concepts of the benzilic acid rearrangement. Benzilic acid rearrangements of the diketones would produce the saccharinic acids, the nature of the acid being determined by the position of dehydration. 

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