Synthesis of L-ascorbic acid

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. 

Bakke and Theander132 described an interesting, new synthesis of L-ascorbic acid by one-step oxidation of 1,2-O-isopropylidene-a-D-glucofuranose to l,2-0-isopropylidene-a-D-xyfo-5-hexulofuranurono-6,3-lactone hydrate (74), followed by hydrolysis of the isopropyli-dene group, and specific, borohydride reduction of the aldehyde group liberated. 

The reaction of L-sorbose with acetone, a step in the synthesis of L-ascorbic acid (vitamin C), takes place in acetone solution [Eq. (41)] (361). 

In this article, an attempt has been made to provide a complete summary of methods developed for the synthesis of L-ascorbic acid. Included are the methods of preparation of precursors in the various syntheses. The syntheses of analogs and isomers of L-ascorbic acid are not covered. Many of the methods used for the preparation of analogs are obvious as they are based on the procedures used for the synthesis... 

The first synthesis of L-ascorbic acid was reported in 1933 by Reich-... 

It is interesting that, when Reichstein and coworkers published the first synthesis of L-ascorbic acid, the correct structure was not yet known, and they considered their synthesis to constitute support of structure 35, earlier proposed by Micheel and Kraft. ... 

In summary, the synthesis of L-ascorbic acid (1, see Scheme 4) by way of D-glucose (8) -> D-glucitol (24) -> L-sorbose (25) -> 2,3 4,6-di-0-isopropylidene-L-xi/(o-2-hexulofuranose (26) -> 2,3 4,6-di-0-iso-propylidene-L-xy(o-2-hexulofuranosonic acid (27) -> 1 may be achieved in excellent yield in commercial practice, it affords 1 in >50% overall yield.255 During the course of the development of this synthesis, a number of papers were published in which the whole sequence was performed, and the overall yield reported. In 1934, the over-... 

Clearly, an improved synthesis of L-ascorbic acid would result from the direct oxidation of L-sorbose (25) to L-xy/o-2-hexulosonie acid (28), thus eliminating the protecting-deprotecting steps currently required in the Reichstein-Griissner synthesis (see Scheme 4). Efforts to perform this oxidation may be divided into two categories, namely, chemical and fermentative. The results of each method will be summarized. 

All synthetic efforts directed towards the synthesis of L-ascorbic acid that have thus far been presented began with the reduction of D-glucose (8) to D-glucitol (24), followed by oxidation atC-5 and C-6. An alternative approach to the synthesis of L-ascorbic acid is first to convert D-glucose (or its equivalent) into D-glucuronic acid (54) (or its equivalent), followed by reduction of 54 at G-1 and then oxidation at C-5, or oxidation of 54 first at C-5 and then reduction at C-l. These options are shown in Scheme 7 in both, formation of L-oty/o-2-hexulo-sonic acid (28) (or its equivalent) results. In this Section, several approaches to the synthesis of L-ascorbic acid that proceed through an intermediate equivalent to 55 will be presented. 

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