Cortisone side chain

Sodium bismuthate Oxidative degradation of cortisone side chains... 

Dry 3/ -acetoxy-ZI8,23-lanostadiene-24-ol-21-oic acid 21- 24-lactone added to a dry suspension of 10%-Pd-on-charcoal in p-cymene, and refluxed 2 hrs. with stirring under N2 3/ -acetoxy-zl8,20(22),23.lanostatrien-24-ol-21-oic acid 21 24-lactone. Y 75%.—This is part of a procedure to obtain the cortisone side chain by degradation. D. Rosenthal et al., Am. Soc. 85, 3971 (1963). 

A third variation of this strategy has been appHed to an enantioselective total synthesis of cortisone. From an appropriately functionalized, scalemic hydrindan that possessed an 11-oxo-group and a masked corticoid side-chain, (+)-cortisol was produced in an 11-step total synthesis (213). 

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

When in the late 1940 s the remarkable therapeutic effects of the glucocorticoids cortisone and hydrocortisone were discovered, new raw materials had to be developed to produce these complicated molecules, and new synthetic methods devised to convert either a 20-ketopregnane or 21-acetoxy-20-ketopregnane to the dihydroxyacetone side-chain characteristic of these corticoids. This latter challenge produced some extremely useful new organic chemical reactions, many of which have wider application outside of steroids. 

Corticoid side chain.5 The final step in a recent total synthesis of cortisone (2) employed a novel double hydroxylation of an enol silyl ether (1) for construction of the side chain. Thus treatment of 1 with 3 equiv. of the peracid and KHC03 in CH2C12 at 0° results in hydroxylation at both Cl7 and C,. 

This method is specific for the 17,21-dihydroxy-20-keto corticosteroids (such as cortisone and hydrocortisone). The method depends upon the action of sulfuric acid with the 17,21-dihydroxy-20-keto groups to give rise to a glyoxal side chain. Subsequent condensation with phenylhydrazine yields a stable yellow color. This reaction was developed by Porter and Silber [98], and its mechanism was elucidated by Lewbart and Mattox [99] as follows ... 

Fluorine at the equatorial 6a position also results in an increase in potency. One scheme for the production of such a compound relies on the shift of the double bond from the 4,5 to the 5,6 position, which follows the formation of an acetal at position 3. The scheme starts with the selective reduction of the 11 ketone in the cortisone intermediate (13-2). Epoxidation of the product (18-1) with a peracid takes place selectively at the unconjugated double bond to give the 5a,6a oxirane (18-2). Treatment of that with hydrogen fluoride in tetrahydrofuran leads to fluorohydrin (18-3). (There is evidence to indicate that the reagent involves an HF THF acid base complex since the omission of THF in at least some cases leads to a complex mixture of rearrangement products [15].) The side chain in fluorohydrin (18-3) is then converted... 

The C-17 side-chain of corticosteroids does not contain a chromophoric group suitable for spectrophotometric measurement, nor does oxidation of the chain lead directly to spectrophotometrically active derivatives. However, the 20-keto group of the 17 a-ketol side-chain, as a chirally perturbed chromophoric group, has an optically active absorbance band in the interval 270-300 nm that is characteristic of the n-7T electronic transition for saturated ketones. An intense positive Cotton effect is observed in the CD spectra see the CD spectra for hydrocortisone and cortisone in Figures 8 and 9. 

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