20-keto-pregnane

With the 4-, 6-" and 15- ° keto steroids the degree of epimerization at C-5 and C-14 depends on the presence of other functional groups and substituents. Exchange of the 16- " and 20- keto pregnanes yields the 17/5-epimer as the main product. 

In a situation where severe steric hindrance e.g., 16,16-dimethyl-20-keto-pregnanes) prevents enol acetate formation, an alternate scheme has been devised. Condensation of ethyl oxalate at C-21 produces, after hydrolysis, the 21-glyoxylic acid this on treatment with acetic anhydride and a strong acid catalyst such as perchloric acid gives both lactone acetates. 

A direct method for introduction of a C-21 acetoxyl group into a 20-keto-pregnane is by reaction with lead tetraacetate at room temperature. Although originally the reaction carried out in hot acetic acid gave low yields, a careful study by Henbest has defined conditions so that yields as high as 86 % can be obtained at room temperature. The preferred solvent is 5 % methanol in benzene, with boron trifluoride etherate as catalyst. With either methanol or benzene, the yield is less than 4%. 

The requisite starting cyanohydrin is readily prepared from a 20-keto-pregnane substitution at C-21 has no effect on the success of this step. However, the stability of the cyanohydrin is markedly dependent on other features of the molecule thus a 3-acetate confers greater stability than the free alcohol, and a 3-ketone is so unstable that subsequent dehydration with phosphorus oxychloride gives poor yields of the A -unsaturated nitrile. 

Reduction of 20-keto pregnanes with complex hydrides gives products which are invariably rich in the 20jS-isomer [34>3 >57] This probably results to a large extent from steric approach control. The preferred conformation about C(i7)-C(2o) in pregnan-20-ones causes the carbonyl C=0 bond to lie nearly eclipsing the C[Pg.319]

Addition of the Reformatsky reagent to the A -20-keto-steroid (255) afforded the pentacyclic derivatives (256) and (257), which could be converted into various 16a-substituted 20-keto-pregnanes/ The 16/S-dimethylaminopregnane (259) has been obtained by cleavage of ring E of the pentacyclic steroid (258) (see... 

In 1980, Tanabe and Hayashi successfully used the Carroll rearrangement in the synthesis of cholesterol and its C-20epimeric diastereomer, 20-isocholesterol, from the readily available 16a,17a-epoxy-20-keto-pregnane (61) (Scheme 8.22) [24]. 

The following technique is described in U.S. Patent 2,541,104. A solution of 2.0 g of 3(a )-hydroxy-21-acetoxy-11,20-diketo-pregnane, which can be prepared as described in Helv. Chim. Acta 27, 1287 (1944), is treated in a mixture of 25 cc of alcohol and 6.4 cc of acetic acid at 0°C with 6.0 g of potassium cyanide. The solution is allowed to warm to room temperature and after 3 hours is diluted with water. The addition of a large volume of water to the alcohol-hydrogen cyanide mixture precipitates a gum which is extracted with chloroform or ethyl acetate. The extract is washed with water, and evaporated to small volume under reduced pressure. The crystalline precipitate (1.3 g) consists of 3(a ),20-dihvdroxy-20-cvano-21-acetoxy-11-keto-pregnane dec. 175° to 185°C. 

A solution of 0.60 g of chromic acid in 1.2 cc of water and 11 cc of acetic acid is added to a solution containing about 1.2 g of 3(0 ),20-dihvdroxv-20-cvano-21-acetoxy-11-keto-pregnane at room temperature. After 1 hour, water is added and the product, which precipitates, is filtered and recrystallized from ethyl acetate to produce 3,1 l-diketo-20-hvdroxy-20-cyano-21-acetoxv-pregnane dec. 214° to 217°C. 

Urinary Pregnane-3a,17,20a-triol and ll-Keto-pregnane-3a,17,20a-triol J. Chromatogr. 36(3) 344-347 (1968) ... 

Recent improvements in the total synthesis of steroids which give as the first tetracyclic products 19-norsteroids bearing a hydroxyl or keto group at C-17 have revived interest in the conversion of androstanes to pregnanes. 

The reaction of 17-keto steroids with hydrogen cyanide (or acetone cyanohydrin) to form a mixture of the 17-cyano-17-hydroxy compounds, followed by dehydration and reaction with methyl Grignard reagent, is one of the earliest methods for the conversion of androstanes to pregnanes. 

The addition of ethoxyacetylene to 17-keto steroids has been discussed earlier. The 17a-ethoxyethynyl-17jS-hydroxy compounds thus produced can be readily converted to 21-mono-oxygenated pregnanes by acid treatment. 

Many of the reactions already discussed for the preparation of bis-oxygenated pregnanes can also be used for the synthesis of 17,20,21-tris-oxygenated pregnanes by proper choice of substrate. Thus, reaction of a 17-vinyl-17-hydroxy steroid or a A -21-hydroxypregnene with osmium tetroxide will give the 17,20,21-triol, and the Stork reaction can be applied to 17a-hydroxy-20-keto steroids. 

Diketo steroids have been prepared by air oxidation of 3-keto-5i5-steroids in potassium /-butoxide-t-butanoF or by hydrolysis of 4,5-epoxy-3-ketones followed by dehydration. However, the most general synthesis is that used by Camerino et al. to prepare Vketo-A-norandrostanes and pregnanes. Hydroxylation of 17a,20.20,21-bismethylenedioxypregn-... 

The most important routes to B-norsteroids involve oxidative fission of 5,6-double bonds to keto acids or keto aldehydes which are then closed to five-membered rings by condensation reactions. Three of the best oxidation methods are exemplified in the following examples chosen from the cholestane, androstane, and pregnane series. 

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