Intermediates ascorbic acid, lactonization

The most significant chemical characteristic of L-ascorbic acid (1) is its oxidation to dehydro-L-ascorbic acid (L-// fi (9-2,3-hexodiulosonic acid y-lactone) (3) (Fig. 1). Vitamin C is a redox system containing at least three substances L-ascorbic acid, monodehydro-L-ascorbic acid, and dehydro-L-ascorbic acid. Dehydro-L-ascorbic acid and the intermediate product of the oxidation, the monodehydro-L-ascorbic acid free radical (2), have antiscorbutic activity equal to L-ascorbic acid. 

The most important oxidation product of L-gulono-1,4-lactone (I) is, without a doubt, L-ascorbic acid (6 vitamin C), and the most important oxidation product of L-gulonic acid (3) is L-xyZo-2-hexulosonic acid (5), which serves as a key intermediate in the commercial production of L-ascorbic acid. The literature covering the methods by which 1 or 3 (or derivatives thereof) has been converted into 6 or 5, as well as other methods for the preparation of 6, has been reviewed,1 and will not be discussed here. 

A survey of the reported syntheses of L-ascorbic acid reveals that derivatives related to 2-keto acid (2) (Scheme 3) are the most frequently used intermediate to L-ascorbic acid. 3-Keto acid (3), keto-lactone (4) (in protected form), and 6-aldehydo-L-ascorbic acid (5) are less frequently used. The use of each of these intermediates (2—5) will be illustrated in the following discussion of the different syntheses of L-ascorbic acid. 

This Cl homologation of osones proved to be valuable in the preparation of L-ascorbic acid analogues (16) as well as in the preparation of radiolabeled L-ascorbic acid (17-20), This synthesis was greatly improved when aldoses were discovered to be directly oxidized to osones with cupric acetate (Equation 1) (21), Subsequently, the conditions were modified so that D-xylose could be oxidized to D-xylosone in 50-55% yield with cupric acetate in methanol. The intermediacy of the imino ether was proved by the isolation of 7 when D-glucosone was treated with potassium cyanide (16), The initial cyanohydrin adduct (3a) easily undergoes cyclization to the imino ether intermediate (aqueous solution for 10 min at room temperature. Scheme 5). This feature will be compared with the conditions required for the lactonization of other intermediates. 

An alternative method of preparing L-ascorbic acid was reported by Bakke and Theander (Scheme 14) (43), In this synthesis D-glucose was first oxidized at C6, then at C5, and then reduced at Cl. This contrasts with the Reichstein-Griissner synthesis in which glucose was first reduced at Cl, then oxidized at C5, and then at C6 to achieve the requisite inverted carbon chain. The key intermediate in the Bakke-Theander synthesis, ketolactone (25) was prepared earlier (44,45) but was not converted to 1. Hydrolysis of 25 afforded 6-aldehydo-L-ascorbic acid (26, aldehydo-L-threo-hex-4-enurono-6,3-lactone) as an unisolated intermediate. Compound 26 was not previously synthesized. The reduction of 26 afforded 1. This synthesis of 1 is used effectively in the preparation of labeled derivatives of 1 (46). It is not useful for the preparation of analogues. 

Chloric acid in conjunction with catalysts, particularly vanadium pent-oxide 204) j has as its principal use the oxidation of aldonic acids or lactones to the 2-keto acids, intermediates in the preparation of ascorbic acid and analogs, as discussed in a preceding section. 

Two new routes to L-ascorbic acid (58) have been described. In one of these, L-galactono-lactone (57) is the precursor, convertible in three steps (Scheme 10) into ascorbic acid, whilst in the other (Scheme 11), the 1,5-anhydro-D-galactitol 59, accessible from D-galactose, was used as an intermediate.73... 

Oxidation of ascorbic acid by singlet oxygen gives L-threonic acid 1,4-lactone and oxalic acid, analogously to the reaction catalysed by ascorbate 2,3-dioxygenase. Intermediates of this reaction are hydroperoxides of ascorbic acid and of dehydroascorbic acid hydrate (Figure 5.29). 

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