L-Ascorbic acid, in synthesis

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%. 

Studies have been made on the individual steps in this synthesis. Acetonation104 of L-sorbose was studied with respect to time, temperature and the presence of metal catalysts, among which aluminum and zinc were found beneficial. Solvent extraction105 was discovered as a means of separating the monoacetone derivative from the desired diacetone-L-sorbose (see page 117). Reichstein and Griissner103 condensed L-sorbose with formaldehyde, with 2-butanone and with benzaldehyde but they found the diacetone derivative to be the most satisfactory intermediate in their ascorbic acid synthesis. A crystalline dicyclohexylidene derivative has also been proposed in this connection.100... 

A second synthesis in which a Ci fragment was coupled with a C5 fragment was reported in which acid chloride (8) was converted to the acyl nitrile (9) by use of silver cyanide (23) (Scheme 6). Hydrolysis and esterification produced ethyl 3,4,5,6-tetra-0-acetyl-DL-xyio-2-hexulo-sonate. The conditions required for the conversion of this material to DL-ascorbic acid will be discussed later. No yields were reported for this reaction sequence. This synthesis has not been used for the preparation of analogues or radiolabeled derivatives of L-ascorbic acid as has the osone-cyanide synthesis first reported (9-12). In contrast to the osone-cyanide synthesis (Scheme 5) in which a 3-ketogulonic acid derivative is produced, the acid chloride-silver cyanide synthesis (Scheme 6) results in the formation of a 2-ketogulonic acid derivative (2a) as an intermediate in the ascorbic acid synthesis. 

Chaudhuri, C. R., and Chatterjee, I. B., 1969, L-Ascorbic acid synthesis in birds Phylogenetic trend, Science 164 435-436. 

Fig. 7. Possible pathways of L-ascorbic acid synthesis in plants. (From Isherwood.)...

L-Ascorbic acid biosynthesis in plants and animals as well as the chemical synthesis starts from D-glucose. The vitamin and its main derivatives, sodium ascorbate, calcium ascorbate, and ascorbyl palmitate, are officially recognized by regulatory agencies and included in compendia such as the United S fates Pharmacopeia/National Formula (USP/NF) and the Food Chemicals Codex (FCC). 

This synthesis was the first step toward industrial vitamin production, which began in 1936. The synthetic product was shown to have the same biological activity as the natural substance. It is reversibly oxidized in the body to dehydro-L-ascorbic acid (3) (L-// fi (9-2,3-hexodiulosonic acid y-lactone), a potent antiscorbutic agent with hiU vitamin activity. In 1937, Haworth and Szent-Gyn rgyi received the Nobel Prize for their work on vitamin C. 

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). 

The isolation of ascorbic acid was first reported by Albert Szent-Gyorgyi (who called it hexuronie add) in 1928. The structure was determined by ITirst and Haworth in 1933, and, simultaneously, Reichstein reported its synthesis. Haworth and Szent-Gyorgyi, who together suggested that the name be changed to L-ascorbic acid to describe its antiscorbutic (antiscnrvy) activity, were awarded the Nobel Prize in 1937 for their studies of vitamin C. 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

This method, utilized simultaneously by Reichstein2 and by Haworth and coworkers3 in the first synthesis of d- or L-ascorbic acid, can be illustrated in detail by reference to the preparation of D-glucoascorbic acid (XV).3... 

The nitriles can also be employed as intermediates in the condensation of ethyl glyoxylate with aJdehydo sugars under the influence of sodium methoxide, leading to the preparation of L-ascorbic acid and similar compounds. Helferich and Peters described the synthesis of D-ascorbic acid (XXVIII) from tetraacetyl-n-xylononitrile (XXVI) presumably the nitrile underwent a type of ZempMn degradation and the n-threose (XXVII) thus formed condensed with the glyoxylic ester. The method... 

Vitamin C Is the Synthetic Vitamin as Good as the Natural One A claim put forth by some purveyors of health foods is that vitamins obtained from natural sources are more healthful than those obtained by chemical synthesis. For example, pure L-ascorbic acid (vitamin C) extracted from rose hips is better than pure L-ascorbic acid manufactured in a chemical plant. Are the vitamins from the two sources different Can the body distinguish a vitamin s source ... 

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