From Androstanes

One of the more readily available plant steroids, dehydroepiandrosterone (DHEA), provides the raw material for conversion to estrone. An early step in converting steroids from plant sources to starting material for modified estrogens comprises obligate expulsion of the methyl group at position 10 that blocks aromatization of the A-ring. 

4-dibromide (2-4). This intermediate, which is not isolated, rearranges spontaneously to the 2a,4a-dibromide in which each of the halogen atoms is actually equatorial. Treatment of 2-5 with a non-nucleophUic base such as 2,4,6-collidine 

Steroid Chemistry at a Glance Daniel Lednicer 2011 John Wiley Sons, Ltd 

A marked improvement on what amounted to pyrolysis consists in treatment of the dienone with strong base. In the case at hand, the carbonyl group at position 17 needs to be protected against attack by the lithio reagent. The ketone at position 17 is therefore first converted to its trimethylenedioxy acetal 2-7 by reaction with propylene-1,3-diol in the presence of a small amount of acid. Treatment of this l,4-dien-3-one with lithium metal in the presence of diphenylmethane leads to the trimethylenedioxy acetal, 2-9, of estrone. The diphenylmethane present in the reaction mixture presumably quenches the extruded methyllithium to prevent its addition to the starting dienone. Treatment with dilute acid then restores the carbonyl group to afford estrone (1-2). 

In the case of the steroid dienone 2-6, the methyl group formerly on Cjo migrates to position 1 on the aromatic ring (3-3). This compound and its derivatives show much of the same biological activities as the corresponding compounds lacking the methyl group. 

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A small set of steroids prepared from androstanes feature a spirobutyrolactone at C17. These agents act as antagonists of aldosterone, the highly oxygenated steroid that controls serum electrolytes and blood volume. The antagonist action of the spirolactones is manifested as diuretic and antihypertensive activity. 

HjjJ mol wi 260.45, C 87.62%, H 12.37%. From androst -ane 3,17-dione fiutenandt Tscherning, Z, FhysjoJ, Chem-229, [85 (1934). From androstane-3,17-diol Steiger ... 

Tosylhydrazones on reaction with alkylithium reagents give olefins in high yield. This new synthesis allowed for exas le the preparation of 16-androstene from androstan-17-one in quantitative yield.Reduction of carbonyl functions to methylene c ui be effected electrochemically or by treatment of the steroid ketones with powdered zinc in acetic anhydride saturated with hydrogen chloride at room temperature." ... 

Labeling studies using 0 applied to the hypoiodites derived from androstan-17P-oF and cyclopentanoP" (Schemes 39 and 40) in which 0-labeled mercury (II) oxide as the source of Ij was used, proved that the 0 was specifically incorporated in the formyl group of the formates, and that no 0 was incorporated in the oxasteroid derived from it. 

Methods for reconstmcting the C-17 side chain from intermediates such as androstendione have been developed. These are used when commercial considerations favor the production of androstanes, but pregnanes are the ultimate goal (25,30). 

The reaction of 6-amino-5-(l,2-diethoxycarbonylhydrazino)pyrimidines with enamines represents another convenient method for the preparation of pteridines. Fusion of 5-(l,2-diethoxycarbonylhydrazino)-2,4,6-triaminopyrimidine (281) with an excess of mor-pholinocyclohexene leads to 2,4-diaminotetrahydrobenzo[g]pteridine, and with the morpholinoenamine (282) from 17/3-hydroxy-5a-androstan-3-one regioselective condensation to the fused pteridine (283) takes place in almost quantitative yield (equation 101) (71CC83). 6-Amino-5-nitroso- and 6-amino-5-phenylazo-pyrimidines react similarly, imitating the Timmis-type reaction (72CPB1428). 

There is no generally reliable rule of thumb to predict whether an axial or equatorial proton will exchange faster. For instance, in the examples discussed above, the slowest rate of exchange is found for the S -axial proton in 5a-androstan-7-one (1) [see(2)-(4)] and the 2fi-equatorial proton in 5a-androstan-l 1-one (5) [see (6)-(9)]. Furthermore, the results of base-catalyzed exchange cannot necessarily be predicted from the corresponding... 

A solution of 3j5-hydroxy-5a-androstan-7-one (10, 50 mg) in methanol-OD (4 ml) is saturated with deuterium oxide containing 5 % sodium deuterioxide (prepared by reacting sodium with deuterium oxide) and heated under reflux for 3 days. (If the heated solution becomes turbid due to supersaturation, a few drops of methanol-OD should be added until a clear solution is obtained. The use of a drying-tube on top of the condenser is advisable to avoid isotope dilution from moisture.)... 

After cooling, the reaction mixture is diluted with ether, the organic phase washed with ice-cold water and dried over anhydrous sodium sulfate. Evaporation of the solvent and crystallization of the residue from ether-hexane gives 6,6,8j5-d3-5a-androstan-3j5-ol-7-one (11) in 84% yield mp 141-142,5° isotopic composition 6% d2,93% da and 1 %... 

Enolizalion of conjugated or /3,y-unsatiirated enones and dienones in O-deiiterated solvents facilitates the introduction of deuterium labels into positions as far as three and five carbon atoms away from a given ketone function. Exchange of the activated hydrogens in androst-4-en-3-one (12) provides a good illustration of the potential of this method. Saturation of the double bond (section V) in the deuterated enone (13) followed by back exchange of the a-deuteriums (section II-B) proves to be an excellent method for the preparation of 6,6-d2-5a-androstan-3-one (15). ... 

A solution of 3jS-hydroxy-5a-androstan-17-one tosylate (193, 60 mg) in tetrahydrofuran (10 ml, freshly distilled from lithium aluminum hydride) is added dropwise to a boiling suspension of lithium aluminum deuteride (60 mg) in tetrahydrofuran (10 ml). The resulting suspension is heated under reflux for 30 min and after cooling the excess reagent is decomposed by the careful addition of a few drops of water. The heating is continued for a few minutes to coagulate the inorganic salts which are removed by filtration... 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

In the androstane and pregnane series the 7-methyl-A -3-ketones (36) are produced from 3j -acetoxy-A -7-ketones (34) with methyllithium, and subsequent Oppenauer oxidation of (35). ° ... 

An ethereal solution approximately 2.5 molar in methyllithium is prepared from 17 ml of methyl iodide and 4 g of lithium metal in 200 ml of anhydrous ether. A mixture consisting of 150 ml anhydrous ether, 3 g (10 mmoles) of 3jS-hydroxy-5a-androstane-ll,17-dione and 60 ml (0.15 moles) of the above methyllithium solution are stirred at room temperature for 40 hr. The reaction mixture is diluted with 100 ml of water and the ether is removed by distillation. Filtration of the chilled aqueous phase yields 2.6 g (77%) of 1 la,17a-dimethyl-5a-androstane-3a,l l/ ,17j5-triol mp 149-154°. Recrystallization from acetone-hexane yields pure material mp 164-166° [a] —5° (CHCI3). 

A total of 3 g (0.13 moles) of sodium hydride is added to a solution consisting of 10 g of 17 -hydroxy-5a-androstan-3-one (36 mmoles) in 200 ml of benzene and 10 ml of ethyl formate. The reaction mixture is allowed to stand under nitrogen for 3 days followed by dropwise addition of 10 ml of methanol to decompose the excess of sodium hydride. The solution is then diluted with 300 ml water and the layers are separated. The basic aqueous solution is extracted with ether to remove neutral material. The aqueous layer is acidified with 80 ml of 3 A hydrochloric acid and the hydroxymethylene steroid is extracted with benzene and ether. The combined organic extracts are washed with water and saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. The residue, a reddish-yellow oil, crystallized from 10 ml of ether to yield 9.12 g (83%) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one mp 162-162.5°. Recrystallization from chloroform-ether gives an analytical sample mp 165-165.5° [a]o 53° (ethanol) 2 ° 252 mjj. (g 11,500), 307 m u (e 5,800). 

A mixture of 3.18 g (10 mmoles) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one, 20 ml dry dimethyl formamide and 0.3 g (13 mmoles) of sodium hydride is stirred for 0.5 hr at room temperature under nitrogen. A total of 1.51 g (12.5 mmoles) of redistilled allyl bromide is added and the mixture is stirred for 1 hr on the steam bath. Aqueous potassium hydroxide (2 g in 5 ml of water) is added and stirring is continued for 1 hr on the steam bath. The reaction mixture is diluted with 50 ml of methylene dichloride followed by careful addition of 300 ml of water. The organic phase is separated and the aqueous phase is again extracted with 50 ml of methylene dichloride. The combined extracts are washed with water, dried over sodium sulfate, filtered and chromatographed on 200 g of silica gel. Elution with pentane-ether (4 1) provides 2a-allyl-17j -hydroxy-5a-androstan-3-one 0.85 g (26%) mp 118-119° [aj 14° (CHCI3), after crystallization from ether-hexane. 

The preparation of 17j -hydroxy-4a-methyl-5a-androstan-3-one (3) which cannot be obtained by direct alkylation or via formyl or oxalyl ketones was achieved by Schaub in 40% yield by the Stork " alkylation procedure. As discussed in the introduction this method proceeds by trapping the A -enolate (2), obtained from (1) and lithium in liquid ammonia, with methyl iodide. 

Estr-5(10)-ene-3a,17 -diol (10 g, 36.2 mmoles) is added over a period of 1 hr to a refluxing mixture consisting of 60 g (0.92 moles) of zinc-copper couple, 350 ml of dry ether and 180 g (54 ml, 0.67 moles) of methylene iodide. After the addition is complete, half of the solvent is removed by distillation and 200 ml dry ether is added. The reaction mixture is then transferred to a sealed stainless steel tube and maintained for 3 hr at 92° before being cooled in an ice bath and poured into 500 ml of saturated aqueous sodium bicarbonate solution. The resultant mixture is extracted with ether and the extracts are dried over anhydrous sodium sulfate and concentrated to yield a solid residue which gives 8.4 g (80%) 5,19-cyclo-5a,10a-androstane-3a,17) -diol mp 161-163° [aJo 40° (CHCI3), on crystallization from acetone. 

To a stirred solution consisting of 5 g (9.45 mmoles) 3, 17) -dibenzoyloxy-5a-androst-7-en-6a-ol in a mixture of 150 ml of dry ether and 150 ml of glyme is added lOg (0.16 moles) of zinc-copper couple and 26.7 (8 ml, 0.1 moles) methylene iodide. The mixture is heated under reflux for 4 hr, cooled to room temperature, diluted with 200 ml of ether and filtered. The filtrate is washed with a saturated solution of sodium chloride and water, and dried over anhydrous sodium sulfate. The ether is removed under reduced pressure and the residue is crystallized from acetone-hexane to yield 4.4 g (86%) of 3, 17 -dibenzoyloxy-7a,8a-methylen-5a,8a-androstan-6a-ol mp 166-167° [ ]d -62° (CHCI3). 

The ready availability and low cost of A -20-keto steroids from the degradation of sapogenins has led to intensive study of methods for the preparation of androstanes via these intermediates. The simplest, most practical and most widely used method on a production scale is the Beckmann rearrangement of -20-oximinopregnenes ... 

Vinyllithium Reaction To a cooled solution of 80 g of 3y -hydroxy-5a-androstan-17-one in 1.5 liters of tetrahydrofuran is added 400 ml of 2 4/ vinyllithium in tetrahydrofuran. The solution is stirred at 0° for 0.5 hr, allowed to warm to room temperature, and stirred an additional hr. Cone ammonium chloride solution is added, and the mixture is concentrated under reduced pressure until a precipitate begins to form. The slurry is poured into water, and the precipitate is filtered and recrystallized twice from methanol, affording 52.2 g (60%) of 17a-vinyl-5a-androstane-3, 17i -diol mp 205-207.5°. 

Overall yields of 37% from pregnenolone acetate to 19-norprogesterone and of 43% from 3 -acetoxy-5a-chloro-6l5-hydroxy androstan-17-one to A io)-19-norandrostene-3,17-dioneii have been reported using 6)5,19-ethers as key intermediates. 

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