L-Sorbose

Manufacture of vitamin C starts with the conversion of sorbitol to L-sorbose. Sorbitol and xyHtol have been used for parenteral nutrition following severe injury, bums, or surgery (246). An iron—sorbitol—citric acid complex is an intramuscular bematinic (247). Mannitol administered intravenously (248) and isosorbide administered orally (249) are osmotic diuretics. Mannitol hexanitrate and isosorbide dinitrate are antianginal dmgs (see Cardiovascular agents). 

Most current industrial vitamin C production is based on the efficient second synthesis developed by Reichstein and Grbssner in 1934 (15). Various attempts to develop a superior, more economical L-ascorbic acid process have been reported since 1934. These approaches, which have met with htde success, ate summarized in Crawford s comprehensive review (46). Currently, all chemical syntheses of vitamin C involve modifications of the Reichstein and Grbssner approach (Fig. 5). In the first step, D-glucose (4) is catalytically (Ni-catalyst) hydrogenated to D-sorbitol (20). Oxidation to L-sotbose (21) occurs microhiologicaRy with The isolated L-sotbose is reacted with acetone and sulfuric acid to yield 2,3 4,6 diacetone-L-sorbose,... 

L-Sorhose to 2-KGA Fermentation. In China, a variant of the Reichstein-Grbssner synthesis has been developed on an industrial scale (see Fig. 5). L-Sorbose is oxidized direcdy to 2-ketogulonic acid (2-KGA) (24) in a mixed culture fermentation step (48). Acid-catalyzed lactonization and enolization of 2-KGA produces L-ascorbic acid (1). 

Reichsteia and Grbssner s second L-ascorbic acid synthesis became the basis for the iadustrial vitamin C production. Many chemical and technical modifications have improved the efficiency of each step, enabling this multistep synthesis to remain the principal, most economical process up to the present (ca 1997) (46). L-Ascorbic acid is produced ia large, iategrated, automated faciUties, involving both continuous and batch operations. The process steps are outlined ia Figure 7. Procedures require ca 1.7-kg L-sorbose/kg of L-ascorbic acid with ca 66% overall yield ia 1977 (55). Siace 1977, further continuous improvement of each vitamin C production step has taken place. Today s overall ascorbic acid yield from L-sorbose is ca 75%. In the mid-1930s, the overall yield from L-sorbose was ca 30%. 

Sterile aqueous D-sorbitol solutions are fermented with y cetobacter subo >gichns in the presence of large amounts of air to complete the microbiological oxidation. The L-sorbose is isolated by crystallisation, filtration, and drying. Various methods for the fermentation of D-sorbitol have been reviewed (60). A.cetobacter suboyydans is the organism of choice as it gives L-sorbose in >90% yield (61). Large-scale fermentations can be carried out in either batch or continuous modes. In either case, stefihty is important to prevent contamination, with subsequent loss of product. 

In the third step, L-sorbose is reacted with acetone and excess sulfuric acid at low temperatures. The sorbose dissolves on conversion into the 2,3-mono-O-isopropjhdene-L-sorbose (2,3 monoacetone-L-sorbose) (MAS), and 2,3 4,6-bis-0-isoprop5hdene-a-L-sorbofuranose... 

Diacetone-L-sorbose (DAS) is oxidized at elevated temperatures in dilute sodium hydroxide in the presence of a catalyst (nickel chloride for bleach or palladium on carbon for air) or by electrolytic methods. After completion of the reaction, the mixture is worked up by acidification to 2,3 4,6-bis-0-isoptopyhdene-2-oxo-L-gulonic acid (2,3 4,6-diacetone-2-keto-L-gulonic acid) (DAG), which is isolated through filtration, washing, and drying. With sodium hypochlorite/nickel chloride, the reported DAG yields ate >90% (65). The oxidation with air has been reported, and a practical process was developed with palladium—carbon or platinum—carbon as catalyst (66,67). The electrolytic oxidation with nickel salts as the catalyst has also... 

FIGURE 7.4 D-Fructose and L-fructose, an enantiomeric pair. Note that changing the configuration only at C5 would change D-fructose to L-sorbose. 

Draw a Fischer projection structure for L-sorbose (o-sorbose is shown in Figure 7.3). 

The main drawback of the system is that the ketone catalyst slowly decomposes during the reaction, which means that 0.2-0.3 equivalents are needed for complete conversion. More robust catalysts, which can be used in 1-3 mol%, have recently been reported, but have not as yet been widely applied [8]. Ketone 1 is commercially available, or can easily be synthesized in large scale in two steps from d-fructose. Ent-1 is obtained in a similar way from L-sorbose. 

L-Sorbose + NADP+ = 5-dehydro-D-fmctose + NADPH (reaction of sorbose dehydrogenase, EC 1.1.1.123)... 

In 1952, Wolfrom and Hilton demonstrated that L-sorbose was also capable of forming dimeric dianhydrides,22 and they postulated sorbofuranosyl and pyra-nosyl cationic intermediates. In 1955, Boggs and Smith23 postulated a fructofu-ranosyl cationic intermediate in the formation of per-O-acetyl ot-D-Fru/-1,2 2,l -p-D-Fru/[di-D-fructose anhydride I (5)] from inulin triacetate. They indicated that three adjacent P-2,l -linked fructofuranosyl units would be required for formation of the dianhydride. 

Treatment of L-sorbose with anhydrous HF80 gave rise to an analogous mixture of products a-L-Sorp-1,2 2,l - 3-L-Sorp (12), (3-L-Sor/ l,2 2,l -a-L-Sorp (13), a-L-Sorf-1,2 2,l -a-L-Sorp, a-L-Sorp-1,2 2,l -a-L-Sorp, ct-L-Soif-... 

When D-fructose and L-sorbose are refluxed with aqueous HC1, dihexulose dianhydrides are formed.91 If the water is replaced by N./V-dimethylformamide, substantially increased yields are obtained and 1,2-linked disaccharides are detected. Higher yields of dianhydrides were obtained from fructose, rather than sorbose, under comparable conditions. Treatment of levan with dilute H2S04 at 60°C yielded92 a-D-Fru/-l,2 2,1 -fi-D-Fru/(5). Presumably, any products that contain 2,6-linkages with large central rings would rapidly isomerize to the more stable 1,2-linked product. 

CjjHjf.NsO 25146-54-7) see Fludarabine phosphate diacetone-2-oxo-L-gulonic acid (C 2H],07 18467-77-1) see Ascorbic acid diacetone-L-sorbose... 

C9H14O9 50-70-4) see Ascorbic acid Isosorbide dinitrate L-sorbose... 

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