Steroids, 12-keto reduction

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

The reduction of 1 l-keto-9 -H steroids gives an lla-ol, due to the fact that ring B or C must be in the boat form. The presence of bromine at the 2a-, 5a- and 12a-positions does not afifect greatly the isomer composition resulting from reduction of 3-, 6- and 11-ketones respectively. When in a 7-keto steroid the bromine is in the 6a-position a mixture of la- and 7 -ols results when the bromine is in the 6 -position only the 7jS-hydroxy compound is obtained. " The presence of bromine in the 16a- or 16 -positions seems to reduce the amount of 17 -alcohol formed. ... 

Reduction of a 16a-bromo-17-ketone (but not the 16 -epimer) is a little less stereospecific than reduction of the 17-keto compound. When a 2a-bromo-3-keto steroid is reduced, at least 78 % of the 3/ -alcohol is obtained. 

The reduction of keto steroids by treatment with chloroiridic acid, or sodium chloroiridate, and trimethyl phosphite has been studied in some detail.Ketones at the 2- and 3-positions are reduced predominantly to the corresponding axial alcohols, while ketones at 4,6,7,11,12,17 and 20 are not affected. The rate of reaction is increased by addition of aqueous sodium hydroxide. Replacement of sodium chloroiridate by tris(triphenylphos-phine)rhodium chloride gives a system which reduces a 3-keto steroid to the... 

A good example is the reduction of 11-keto steroids (69) which gives only the llJ -hydroxy derivatives (70) with metal deuterides. Generally, the 1 la-alcohols are obtained in good yield by reduction with lithium in liquid ammonia-methanol mixtures. By analogy, llj -dj-lla-alcohols (71) are expected when a deuterioammonia-methanol-OD system is used. (For an alternate preparation of an 11/5-dj-l la-hydroxy steroid, see section III-C). 

With certain carbonyl compounds, however, such as 3-keto steroids, the isotopic composition is poor due to the rapid exchange of the activated a-hydrogens in the substrate prior to reduction. The corresponding alcohols, in their thermodynamically more stable configuration, are usually found as... 

This reduction is not as suitable for sterically hindered ketones, since in these cases the alcohol is the major product. The reduction of 11- and 12- " keto steroids, for example, is usually very slow. Furthermore, the 11-keto steroid (76) yields only about 10% of the 11,1 l-d2 labeled analog (77), the main product being the 1 IjS-dj-l la-hydroxyl derivative (78). ... 

Three different methods have been discussed previously (sections III-C,III-D and IV-A) for the replacement of a carbonyl oxygen by two deuteriums. However, in the conversion of a 3-keto steroid into the corresponding 3,3-d2 labeled analog, two of the three methods, electrochemical reduction (section ni-C) and Raney nickel desulfurization of mercaptal derivatives (section IV-A), lead to extensive deuterium scrambling and the third method, Clemmensen reduction (section III-D), yields a 2,2,3,3,4,4-dg derivative. 

A pertinent example is the reduction of 5a-androst-8-en-l 1-one (154) which yields 8 -di-5a-androstan-l 1-one (155) in 93% isotopic purity. Saturation of A -6-keto steroids gives equally good results for labeling the 8/5-position. ... 

A recent modification of this technique utilizes A,A-d2-propylamine as the solvent for the lithium reduction, thereby eliminating the inconveniences associated with the preparation and handling of liquid deuterioammonia. Under these conditions the reaction can be carried out at room temperature and less overreduction of the carbonyl group is observed. For example, the reduction of A" -3-keto steroids (159) under these conditions, followed by back exchange in protic media, leads to the corresponding 5a-di-3-ketones (160) which exhibit good isotopic purity. ... 

Some advantages of this reaction are high yield if the tosylate is in a sterically accessible position excellent isotopic purity of the product (usually higher than-95%) and perhaps most important, access to stereospecifically labeled methylene derivatives. For example, deuteride displacement of 3j -tosylates (183) yields the corresponding Sa-d derivative (185) in 96-98% isotopic purity. Application of this method to the labeled sulfonate (184), obtained. by lithium aluminum deuteride reduction of a 3-ketone precursor (see section HI-A) followed by tosylation, provides an excellent synthesis of 3,3-d2 labeled steroids (186) without isotopic scrambling at the adjacent positions. The only other method which provides products of comparable isotopic purity at this position is the reduction of the tosyl-hydrazone derivative of 3-keto steroids (section IV-B). 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia " reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for... 

Both sodium acetylide in xylene (Air Reduction Corporation) and lithium acetylide-ethylenediamine complex (Foote Mineral Co.) are now commercially available, and have been used successfully for the ethynylation of 17-keto steroids. 

In keto steroids the reductions were also achieved by electrolysis in 10% sulfuric acid and dioxane using a divided cell with lead electrodes (yields 85-97%) [862], hy specially activated zinc dust in anhydrous solvent (ether or acetic anhydride saturated with hydrogen chloride) (yields 50-87%) [155, 86J], and by the above mentioned reduction of tosylhydrazones with sodium borohydride (yields 60-75%) [811]. 

It is worth saying that both lacking of selectivity in the A4 olefinic moiety hydrogenation and increasing of the axial epimer in 3 keto-derivatives saturation following the donor steric demand are typical aspects of steroid reduction by means of complex hydrides8. 

Reductive desulfonylation.1 A stereocont rolled method for addition of the steroid side chain to a 17-keto steroid is outlined in scheme (I). The various steps proceed selectively to the sulfone 5. Reductive desulfonylation of 5 with Na/Hg, Na2HP04 in CH3OH gives the desired 6 (57% yield) and the undesired alkene in a 2 1 ratio. The desired stereoselectivity was obtained with lithium in ethylamine. The final step was hydrogenation of the 17(20)-double bond to give a protected cholesterol (7). 

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