Corticosteroids Cortisone synthesis

Pregniines. In 1944, Sarrett completed the first partial synthesis of cortisone (172). Like many of the early syntheses of corticosteroids, Sarrett began with the a bile acid, deoxychoHc acid (14). Because bile acids are isolated from animal sources, their supply is by necessity limited (173). Following these early syntheses, several improvements and innovations have resulted in a number of industrial syntheses of cortisol and other corticosteroids. 

However, corticosteroids and their metabolites (1) were early recognized as possessing powerful antiinflammatory and immunomodulatory properties. Even prior to 1950, reports of the antiarthritic properties of cortisone (1) by Hench and co-workers (2) indicated the potential for these compounds to reduce the suffering of patients with inflammatory diseases. This awareness, combined with the first synthesis of naturally occurring glucocorticoids (11-desoxycorticosterone), led not only to the massive increase in research in the area of steroid synthesis and physiology, but to a Nobel prize in 1950 for early steroid pioneers Hench, Reichstein, and Kendall. 

In a remarkably simple synthesis95 of the corticosteroid side chain (Scheme 10) the oxime (208) was refluxed with acetic anhydride in pyridine to form the enamide (209) which with lead tetra-acetate in benzene under strictly anhydrous conditions gave the acetylimino-compound (210) (90%). Isomerization of (210) with acetic acid-trichloroacetic acid formed the enamide (211) (100%) further lead tetra-acetate oxidation gave the acetylimine (212) (84%). Compound (212) was quantitatively hydrolysed with aqueous acetic acid to the a-acetoxy-ketone (213) and thus led to a rapid synthesis of cortisone. These reactions are essentially one pot syntheses. 

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

Glucocorticoids also have antiallergic properties, as a result of and by an inhibition of the synthesis of histamine by mast cells and basophils. Of the naturally occurring corticosteroids, only cortisol and corticosterone possess glucocorticoid activity, with cortisol the most effective. Cortisone and 11-dehydrocorticosterone lack direct glucocorticoid activity, but have potential glucocorticoid activity because they can be metabolixed to cortisol and corticosterone, respectively. 

Studies of the incorporation of labeled amino acid and labeled amino acid precursors (Krebs cycle intermediate or bicarbonate) in diaphragm have dissociated the effect of cortisone on amino acid penetration from its effect on amino acid incorporation and protein synthesis. The results demonstrated that adrenalectomy is without effect on the amino acid uptake by isolated diaphragm. In contrast, corticosteroids inhibit amino acid uptake by the isolated diaphragm. Adrenalectomy enhances and cortisone depresses the incorporation of " C-labeled amino acid, glucose, bicarbonate, and dicarboxylic acid into protein of the diaphragm. It has also been found that corticosteroids decrease amino acid incorporation into proteins in... 

As we have described elsewhere [9], we were able to use this radical relay process to complete a successful synthesis of cortisone. With another appropriate template we were able to achieve a selective chlorination at C-17 of the steroid, which permitted us to remove the steroid side chain [10]. Recent work in Germany [11] has resulted in a somewhat easier sequence for converting the 17-chloro steroid derivative to a useful intermediate in which the side chain has been removed. It remains to be seen whether the steroid reactions by which we can produce corticosteroids or remove steroid side chains and generate useful intermediates actually lead to practical transformations of industrial interest. These reactions are under active investigation in several companies. 

Corticosteroids (e.g., cortisone, prednisone, dexamethasone) induce cataracts in humans and rabbits, possibly as a result of changes in sodium and potassium transport or synthesis of proteins in the lens. 

The steroids we will consider as targets for synthesis are shown here (Steroids-1). Cholesterol (and derivatives) is an important component of cell membranes. Gallstones are mainly cholesterol. It is one of the steroids most familiar to the layperson. Other steroids of much interest include the sex hormones (structurally related to progesterone) and the corticosteroids, represented here by cortisone. 

---