Saccharinic acids preparation

All of the 4-carbon saccharinic acids possible have been prepared and characterized.132 The 4-carbon metasaccharinic acid has been encountered frequently,1,133-137 and a racemic mixture of the 2-methyl-glyceric acids (2,3-dihydroxy-2-methylpropanoic acids) was obtained from 4-O-methyl-D-threose.136... 

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. 

The 1-deoxyosone represents the most elusive of the three intermediates, but also the most important from the standpoint of food flavor and aroma production. A large number of methyl-containing furanones, pyrones and related compounds are found in food preparations that are consistent with having been formed from this intermediate. A synthesis of this material was reported some years ago by Isuzu, et al. (10), but the yields were very low and the product was not well characterized. The workers reported that the compound gave one of the two reported isomers of "saccharinic acid", the expected degradation product in alkaline solution, along with fragmentation products. This material will be addressed (vide infra) in a later section. 

Shortly after the discovery of Peligot s a -D-glucosaccharin, Dubrun-faut reported that the calcium salt of a monobasic acid resulted from the action of lime-water on maltose. Cuisinier named the acid isosaccharinic acid, after he had prepared from it a crystalline lactone (CeHioOt) isomeric with Peligot s a -D-glucosaccharin. The name was expanded to a -D-iso-saccharinic acid after Nef obtained evidence of the concurrent formation of its epimer, /3 -D-isosaccharinic acid, in the hexose-alkali reaction. 

At this stage, the possible presence of a branched-chain saccharinic acid in Kiliani s preparation was supported only by (a) the properties of the barium salt of the hydroxyhexanoic acid obtained from it on reduction and (b) the reported oxidation of parasaccharinic acid with nitric acid to a tribasic acid. The latter evidence was retracted by Kiliani in his final report on the matter, when he stated that the previous identification of hydroxycitric acid was in error and that this tribasic acid is, in fact, ( — )-tartaric acid. In addition, he now observed that oxidation of parasaccharinic acid with nitric acid, followed by reduction with hydriodic acid and red phosphorus, gives a low yield of adipic acid. 

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. 

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. 

In 1909, Kay reported the preparation of a small quantity of the levorotatory potassium salt of this saccharinic acid from d-a-methylisoserine (XLV). Treatment of d-a-methylisoserine (XLV) with nitrosyl bromide gave 3-bromo-2-hydroxy-2-methylpropanoic acid (XLVI). The latter, on... 

Since the impractical feature of Melikoff s synthesis of the saccharinic acid (Vab) was the long and time-consuming preparation of 3-chloro-2-... 

The saccharinic acid was next prepared in 32 % yield from the halogen acid (XLIII) by treatment with silver oxide, but this approach was abandoned when good results were obtained from the acetol-form-ester. Reaction of l-chloro-2-propanone (XLVII) with sodium formate produced the monoformate of l-hydroxy-2-propanone (XLIX) which, through the addition of hydrogen cyanide and hydrolysis of the resulting cyanohydrin of l-hydroxy-2-propanone (L), yielded the desired racemic saccharinic acid (Vab). 

With sufficient quantities of the dl saccharinic acid thus available, many salts, as well as the crystalline phenylhydrazide, were prepared. All attempts at the resolution of this racemic acid by means of strychnine, quinine, or brucine failed to give, on hydrolysis of the alkaloid salts, an optically active acid. However, Glattfeld and Sherman were inclined to beheve that resolution had actually been accomplished by means of... 

Of the five positional isomers of the four-carbon saccharinic acids theoretically possible, 3-hydroxy-2-(hydroxymethyl)propanoic acid (VI) is the only one that lacks an asymmetric carbon atom and is optically inactive and unresolvable. The first attempt at its synthesis, by Glattfeld and cowork-ers, " was by a direct method. The reaction of 2-chloro-2-deoxyglyceritol (LII) [prepared from allyl alcohol (LI) by reaction with hypochlorous acid] with cyanide ion and subsequent hydrolysis of the anticipated nitrile (LIII) should have produced the desired 3-hydroxy-2-(hydroxymethyl)-... 

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. 

The following Tables give the melting points and optical rotations of the four-carbon saccharinic acids and their derivatives thus far prepared. 

Lactic acid occurs amongst the products of the action of alkali on hexoses. From 1 mole of D-glucose, treated at 25°C. with benzyltrimethylammonium hydroxide, Evans reported the production of 1.2 moles of racemic lactic acid (60 % of a theory of 2 moles per mole hexose). The substance apparently can be obtained by the action of alkali on any sugar (inclusive of trioses, pentoses, disaccharides, etc.) (99). Its preparation from sucrose under conditions of high temperature and pressure has been extensively studied from the viewpoint of potential industrial application. Lactic acid may be considered as the saccharinic acid (see below) related to glyceraldehyde and may arise from the rearrangement of a triose fragment. 

Chiral A-substitutcd benzisothiazole-3-one-1,1-dioxide (saccharin) derivatives 258 are synthesized via the direct ortho-lithiation of 3-A-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA <06TL6405>. Compounds 257 are readily prepared from (X)-amino acids. 

The sweetening agent saccharin is also derived from a sulphonamide it is prepared from toluene-o-sulphonamide by oxidising the CHs-group to carboxyl with permanganate ring closure is subsequently brought about by the action of concentrated hydrochloric acid ... 

The best preparative method of obtaining terephthalic acid is to oxidise the sodium salt of p-toluic acid with permanganate at the temperature of the water bath. In the same way toluene can be converted into benzoic acid, and an important technical example of this reaction is the oxidation, of o-tolylsulphonamide to saccharin. 

Zajic has described an extremely convenient and high yielding preparation of Al-bromo-saccharin, which is an excellent source of electrophilic bromine, by treatment of saccharin with KBrOs and sulfuric acid in aqueous acetic acid <99SC1779>. 

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