Reichstein-Griissner synthesis

Reichardt s dye, 26 854 Reichert cone, 16 632 Reich process, 4 810 Reichstein-Griissner synthesis, 26 401 of ascorbic acid, 25 752-753, 754, 755-758, 782 Reich test, 23 665 Reid vapor pressure (RVP), 22 396 ... 

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. 

Uniformly labelled 1 was prepared by the Reichstein-Griissner synthesis (see Scheme 4), starting with unifonnly labelled D-glu-cose.597-599 L-[2,3,4,5,6-14C]Ascorbic acid was prepared 800 from L-[U-14C]xylose by way of L-threo-pentos-2-ulose (9) (see Scheme 2). The L-[U-14C]xylose was prepared from D-[U-,4C]glucitol by using the route shown in Scheme 21. 

There are a total of three ascorbic acid processes either in place or in late stages of development with firm expectations of commercialization (i) the traditional chemical Reichstein-Griissner synthesis (ii) the two-step fermentation process to 2-ketogulonic acid with subsequent chemical esterification/lactonization to ascorbic acid and (iii) the one-step fermentation to 2-ketogulonic acid with the same last chemical step. Figure 20.8 and Table 20.3 provide an overview of the three processes. 

An alternative method for protecting L-sorbose (19) was reported (41) and is shown in Scheme 12. No yields were reported and it appears to offer no advantages over the Reichstein-Griissner synthesis. 

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. 

In 1923 the bacterium Acinetobacter suboxydans was isolated and, starting in 1930, was used for the industrial oxidation of L-sorbitol to L-sorbose in the Reichstein-Griissner synthesis of vitamin C[39]. Bayer uses the same type of reaction, but instead of Acinetobacter the bacterium Gluconobacter suboxydans is used in the oxidation of N-protected 6-amino-L-sorbitol to the corresponding 6-amino-L-sorbose, which is an intermediate in miglitol production (Fig. 19-7). 1-Desoxynojirimydn is produced by chemical intramolecular reductive amination of 6-amino-L-sorbose. In contrast, the... 

AH of the vitamins, except Vitamin B12, are produced nowadays by chemical syntheses. Many of them are also obtained via biotechnological processes (Vitamins Bj, Bg, B12) or isolated from natrual products (Vitamins A, D, E, K). For Vitamin C, the exclusively chemical process (the Reichstein-Griissner synthesis) has been replaced by a mixed chemical/fermentation procedure. 

Reichstein-Griissner Sorbitol Fermentation Glucose Fermentation synthesis... 

The Reichstein-Griissner process, developed in 1934, takes in all five chemical steps (hydrogenation, fermentative oxidation, acetonization, oxidation, and hydroly-sis/rearrangement) (Table 20.3). Over the course of the whole synthesis there are 17-20 different downstream processing steps, six solid-handling steps, and at least seven different solvent systems to handle. The overall yield is about 55%, and overall cycle time is around three days. Such values clearly suggest possible improvement in the process towards ascorbic acid. 

Synthesis of vitamin C (ascorbic acid) is conventionally performed via the Reichstein-Griissner procedure, which involves the fermentation of glucose followed by five chemical steps. Cerestar/ BASF recently developed a new process that consists of one fermentation step and two simple chemical steps (via 2-keto-L-gluconic acid). It is predicted that soon a fermentation process will be developed to convert glucose into vitamin C in a single step, eliminating several recovery steps and reducing extraction solvents. 

The following is a summary of the relevant chemistry that was known at the time when Reichstein and Griissner developed this synthesis, as well as a summary of the subsequent modifications to this approach. Each step is discussed separately. 

Synthesis (from D-glucose) T. Reichstein and A. Griissner, Helv. Chim. Acta, 1934, 17, 311. 

Emil Fischer first described the condensation of D-fructose with acetone in 1895, and most of the early work on cyclic acetals of ketoses was performed with D-fructose. In 1934, Reichstein and Griissner published their classic synthesis of L-ascorbic acid (vitamin C), in which L-sorbose was converted into 2,3 4,6-di-0-isopropylidene-a-L-sorbofuranose or other di-alkylidene acetals. The emphasis of research activity then shifted to L-sorbose, and to the elucidation of an optimal procedure for preparing such diacetals. At about the same time, Levene and Tipson used isopropylidene acetals as derivatives for the purification of L-cri/thro-pentulose (as the di-isopropylidene acetal) and D-thrco-pentulose (as the monoisopropyli-dene acetal). Soon thereafter, Reichstein and coworkers used diisopropylidene acetals of D- and L-psicose, and D-tagatose, to purify the respective sugars. 

Reichstein and Griissner also prepared di-O-benzylidene and di-O-(2-butylidene) acetals of L-sorbose, and found them to be useful intermediates in synthesis of L-ascorbic acid. By analogy, therefore, their structures are 2,3 4,6-di-0-benzylidene-a-L-sorbofuranose (30) and 2,3 4,6-di-0-(2-butylidene)-a-L-sorbofuranose (102). 

Reichstein T, Griissner A, Oppenauer A. Synthesis of d-ascorbic acid (d-form of vitamin C). Helv Chim Acta 1933 16 561-565. 

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