Cortisone side chain synthesi

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). 

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,. 

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. 

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. 

The Monsanto workers have also considerably improved the last stages of the synthesis, the conversion of compounds (349) and (326) into cortisone (334) and cortisol (357). A distinguishing feature of these synthesis is the introduction of a dihydroxyacetone side chain without previous protection of the A -3-oxo grouping in ring A [1034-1037] (Scheme 112). 

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