Dehydro-oxidation

A steroid very closely related structurally to cholesterol is its 7 dehydro derivative 7 Dehydrocholesterol is formed by enzymatic oxidation of cholesterol and has a conju gated diene unit m its B ring 7 Dehydrocholesterol is present m the tissues of the skin where it is transformed to vitamin D3 by a sunlight induced photochemical reaction... 

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 reversible oxidation of L-ascorbic acid to dehydro-L-ascorbic acid is the basis for its known physiological activities, stabiUties, and technical apphcations (2). The importance of vitamin C in nutrition and the maintenance of good health is well documented. Over 22,000 references relating only to L-ascorbic acid have appeared since 1966. 

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. 

Chemical Properties. The most significant chemical property of L-ascorbic acid is its reversible oxidation to dehydro-L-ascorbic acid. Dehydro-L-ascorbic acid has been prepared by uv irradiation and by oxidation with air and charcoal, halogens, ferric chloride, hydrogen peroxide, 2,6-dichlorophenolindophenol, neutral potassium permanganate, selenium oxide, and many other compounds. Dehydro-L-ascorbic acid has been reduced to L-ascorbic acid by hydrogen iodide, hydrogen sulfide, 1,4-dithiothreitol (l,4-dimercapto-2,3-butanediol), and the like (33). 

Metal oxides, sulfides, and hydrides form a transition between acid/base and metal catalysts. They catalyze hydrogenation/dehydro-genation as well as many of the reactions catalyzed by acids, such as cracking and isomerization. Their oxidation activity is related to the possibility of two valence states which allow oxygen to be released and reabsorbed alternately. Common examples are oxides of cobalt, iron, zinc, and chromium and hydrides of precious metals that can release hydrogen readily. Sulfide catalysts are more resistant than metals to the formation of coke deposits and to poisoning by sulfur compounds their main application is in hydrodesulfurization. 

In extension of this work, Sugasawa and Yoshikawa have shown that d/- omolaudanosoline (XIII), on oxidation by chloranil in presence of acetic acid, also gives rise to a dehydro-product, which on methylation furnishes 2 3 11 12-tetramethoxy-8-methyl-6 7 15 16-tetrahydro-5 18 9 14-dibenzopyridocolinium salts (XIV). 

Ascorbic acid is a reasonably strong reducing agent. The biochemical and physiological functions of ascorbic acid most likely derive from its reducing properties—it functions as an electron carrier. Loss of one electron due to interactions with oxygen or metal ions leads to semidehydro-L-ascorbate, a reactive free radical (Figure 18.30) that can be reduced back to L-ascorbic acid by various enzymes in animals and plants. A characteristic reaction of ascorbic acid is its oxidation to dehydro-L-aseorbie add. Ascorbic acid and dehydroascor-bic acid form an effective redox system. 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

The ethyl acetate solution is then washed with water, dried and evaporated. To remove any selenium still present, the residue is dissolved in 200 cc of methanol and mixed with 100 g of iron powder and 2 g of active carbon. The mixture is heated for 30 minutes with stirring under reflux, then filtered with suction, washed with methanol and the solution evaporated in vacuo. The residue is then chromatographed on 900 g of aluminum oxide. The residues of the evaporated benzene and ether fractions are treated with active carbon in methanol or acetone, evaporated again, and the residue recrystallized from a mixture of acetone and ether. There are obtained 17.5 g of pure 1-dehydro-17a-methyl-testosterone which melts at 163° to 164°C. 

Thiamin has a central role in energy-yielding metabo-hsm, and especially the metabohsm of carbohydrate (Figure 45-9). Thiamin diphosphate is the coenzyme for three multi-enzyme complexes that catalyze oxidative decarboxylation reactions pymvate dehydrogenase in carbohydrate metabolism a-ketoglutarate dehydro-... 

It has long been recognized that ascorbate levels are low in patients with RA (Lunec and Blake, 1985) and ascorbate is predominantly found in the dehydro form. The presence of increased dehydroascorbate has been suggested to indicate its rapid oxidation by stimulated PMNs (Halliwell and Gutteridge, 1990). When ascorbate concentrations are lower than about 20 /tmol/1, as can occur in rheumatoid synovial fluid, the Fe(III) reducing effects of ascorbate outweigh its radical-scavenging effects. Ascorbate then causes increased OH formation and promotes lipid peroxidation (Blake et al., 1981). 

A chemical reaction subsequent to a fast (reversible) electrode reaction (Eq. 5.6.1, case b) can consume the product of the electrode reaction, whose concentration in solution thus decreases. This decreases the overpotential of the overall electrode process. This mechanism was proposed by R. Brdicka and D. H. M. Kern for the oxidation of ascorbic acid, converted by a fast electrode reaction at the mercury electrode to form dehydro-ascorbic acid. An equilibrium described by the Nernst equation is established at the electrode between the initial substance and this intermediate product. Dehydroascorbic acid is then deactivated by a fast chemical reaction with water to form diketogulonic acid, which is electroinactive. 

Microbiological oxidation has proven of enormous value in steroid chemistry, often affording selective means of functionalizing remote and chemically inactivated positions. It will bear mentioning that the 11-oxygen for all commercially available corticoids is in fact introduced by such a reaction carried out on plant scale. Preparation of the 1-dehydro analogue of 207 involves biooxidation to introduce the 16-hydroxyl. Incubation of 6a-fluoroprednisolone... 

Introduction of a hydroxyl group into the protoberberine skeleton was successfully carried out by the hydroboration-oxidation method. Dihydro-berberine (90) was converted to ( )-epiophiocarpine (91) as a major product along with ( )-ophiocarpine (92) (Scheme 22) (71). 5-Hydroxyprotober-berines 94 and 95 were obtained from the 5,6-dehydro compound 93 (50) synthesized from papaverine via 54 (72). 

---