5a-Cholestane-3-one

Fig. 1 Fluorescence scans of a blank (A) and of a mixture (B) of cholesterol (2), coprostanol (3), 4-cholesten-3-one (4), 5a-cholestan-3-one (5) and coprostanone (6), start (1), solvent front (7).

The presence of an a-bromo substituent may cause anomalies. With NaBH4, 2a-bromo-5a-cholestan-3-one gives a mixture of epimers, in which the 3p-o predominates. 4 -Bromo-17)5-hydroxy-5)5-androstan-3-one acetate gives 25% of the 315,4 -bromohydrin and 34% of the 3a,4)5-compound. Reduction of 7a-bromo-3)5,5a-diacetoxycholestan-6-one gives exclusively 7a-bromocholestane-3)5,5a,6a-triol 3,5-diacetate,whereas reduc-... 

A solution of 0.2 g of cholestenone and 0.47 g of (< 3P)3RhCl in 150 ml of acetone is stirred under a hydrogen atmosphere for 3 days. The solvent is evaporated and the residue separated by thin layer chromatography to afford 5a-cholestan-3-one in 25-35% yield. ... 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

The reaction of A -bromosuccinimide with 5a-cholestan-3-one enol acetate in aprotic conditions, described by Green and Long, is probably free radical in character cf. ref. 69). 

An illustration of the difference in reactivity of a-and / -halides is provided by the ready elimination of 1,4a-dibromo-5a-cholestan-3-one to 4a-bromo-5a-cholest-l-en-3-one in collidine at room temperature. Calcium carbonate in refluxing DMA is necessary to complete the dehydrobromination to the l,4-dien-3-one. ... 

The reduction of 2-a-halo-5a-cholestan-3-ones (142) is illustrative the yield rises with decreasing atomic number of the halogen, °°... 

To a solution of 2a-bromo-5a-cholestan-3-one (7.1 g, 15.2 mmol) in 175 ml dry acetone is added dropwise a solution of potassium ethyl xanthate (2.6 g, 16.2 mmol) in 90 ml acetone. The reaction mixture is stirred at 20° for 12 hr and then evaporated to dryness under vacuum. The resulting solid is treated with 100 ml hexane to dissolve the organic material and the inorganic salts are removed by filtration. The hexane filtrate is concentrated under vacuum and the resulting yellow solid ca. 7.5 g) is crystallized from chloroform-ethanol to give the xanthate (137) as white needles, ca. 5 g mp 114-115°. 

Sodium Borohydride Reduction of Ethyl 5a.-Cholestan-3-one 2a.-Xanthate ... 

To a mixture of ethyl 5a-cholestan-3-one 2a-xanthate (2 g, 3.95 mmol) and 100 ml methanol is added sufficient ether to completely dissolve the solids. Sodium borohydride (90 mg, 2.36 mmol) is added directly to the reaction flask and the solution is stirred at room temperature for 4 hr. (The use of an excess of sodium borohydride and an extended reaction time produces 5oc-cholestan-2a,3a-thiirane.) The reaction is diluted with 200 ml ether and washed several times with ca. 100 ml water, dried (MgS04) and the solvent is removed under vacuum. The crude sticky gum is chromatographed on a column of 85 g silicic acid. The hexane eluates contain 5a-cholest-2-ene. Ethyl 5a-cholestan-3a-ol 2a-xanthate is obtained in ca. 30% yield by subsequent elution with benzene hexane (1 7) and the desired ethyl 5a-cholestan-3 -ol 2a-xanthate is eluted with ether hexane (1 3) in ca. 30% yield. 

The reaction of Grignard reagents with the keto group of 5a-cholestan-3-one (7) was first described in 1937/ In a later study, Barton obtained the two epimeric tertiary alcohols (8) and (9), in a ratio of 40 60 by exposing (7) to the action of methyl Grignard reagent. 

Gemdialkylated steroids are obtained as the major product when the alkylation is carried out under forcing conditions. Thus a good yield of (3) is obtained on methylation of 5a-cholestan-3-one with a large excess of potassium t-butoxide and methyl iodide. " ... 

Interestingly, introduction of a 7,8-double bond into 5a-cholestan-3-one leads to methylation at the 4a-position. ... 

A solution of 0.7 g (18 mmoles) of potassium in 35 ml of /-butanol is added to a boiling solution of 5 g (13 mmoles) of 5a-cholestan-3-one in 50 ml of benzene and 25 ml of /-butanol. A total of 5 ml (11.4 g, 80 mmoles) of methyl iodide in 50 ml of benzene is then added and refluxing is continued for 3 min. The solution is cooled, ice is added and the product is isolated by extraction with ether. The crystalline residue in light petroleum solution is chromatographed on 300 g of alumina. Elution with light petroleum yields initially 0.55 g (10%) of 2,2-dimethyl-5a-cholestan-3-one mp 111-113° [o(]d 77° (CHCI3), after crystallization from ether-methanol. Further elution affords 1.01 g (20%) of 2a-methyl-5a-cholestan-3-one mp 119-120° [a]o 32° (CHCI3), after crystallization from ether-methanol. 

The product, isolated as above, is dissolved in pentane solution and chromatographed on 100 g of alumina. The initial fraction eluted with pentane, yields 1.02 g (48%) of 2,2-dimethyl-5a-cholestan-3-one mp 111-113°, after crystallization from ether-methanol. The subsequent fraction, eluted with pentane and pentane-benzene (9 1) gives 0.12 g (6%) of 2a-methyl-5a-cholestan-3-one mp 119-120°, after crystallization from methanol-ether. 

The position of the keto group of A-homo-5a-cholestan-3-one (5b) was determined by Nelson and Schut by an unambiguous synthesis of ketone (5b) involving bis-homologation of 2,3-seco-5a-cholestane-2,3-dioic acid (8) using the Arndt-Eistert sequence [(9) (11)]. 

In the latter process Dieckmann cyclization of diester (11) using high dilution conditions failed. However, A-homo-5a-cholestan-3-one (5b) identical to the product of diazomethane ring enlargement of (lb) was obtained in 35 % yield when diester (11) was hydrolyzed to the bis-homo diacid and this converted to the thorium salt and pyrolyzed. 

Meakins and Morris recently reinvestigated the reaction of 5a-cholestan-3-one (lb) with an excess of diazomethane and observed the same results reported by Nelson and Schut. Using preformed diazomethane in ether-methanol, Meakins and Morris found the reaction very slow. However, in the presence of potassium hydroxide, ring expansion proceeds smoothly. The role of the base in markedly increasing the reaction rate has not been explained. 

Although at equilibrium the j5,y-tautomer (16a) is preferred, some of the conjugated enone (17) can be obtained by acid-catalyzed equilibration. Hydrogenation of the A-homo-enone (16a) gives a mixture from which A-homo-5a-cholestan-3-one (5b) can be isolated. 

Oxidative rearrangement of 5a-cholestan-3-one (62) with hydrogen peroxide and a catalytic amount of selenic acid affords 2a-carboxy-A-nor-5a-cholestane, isolated in about 35 % yield as the methyl ester (63)." However, the reaction gives a complex mixture of A-nor- and seco-acids, and under... 

Photolysis of a-diazoketones has also been used to prepare A-norsteroids. Results in the A-nor series support the ketene intermediate invoked for the assignment of the 16) -configuration to the D-nor acids. Thus, irradiation of 2-diazo-5a-cholestan-3-one (99) gives 2/ -carboxy-A-nor-cholestane (100, R = H) in 45 % yield. ... 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

Cholestane-3/3,5a-diol 3-acetate, 397 Cholestane-4a,5a-diol 4-tosylate, 398 Cholestane-5a,6a-diol 6-tosylate,394 5a-Cholestan-2-one, 57, 88, 427 10(5 4 H)ijAeo-Cholestan-5-one, 398 10(5 6)ij ieo-Cholestan-5-one, 392, 394 5a-Cholestan-3-one cyanohydrin, 359 5a-Cholestan-3-one cyanohydrin acetate, 360 5a-Cholestan-2a,3a-oxide, 42 5a-Cholestan-2/3,3/3-thiirane, 43 Cholest-5-ene-3, 19-diol, 268 Cholest-5-ene-3, 25-diol, 71 5(10->l/3H)flfc eo-cholest- 10(19)-ene-3/8,5a-diol 3-acetate, 397, 398 Cholest-4-ene-3,6-dione, 105 Cholest-4-en-3-one, 318 Chromium trioxide, 147, 150 5a-Conanine-3/3-ol-ll-one 3-acetate, 259 Cupric bromide, 210, 211 Cuprous chloride-catalyzed conjugate addition, 76, 80... 

Dimethyl-5a-cholestan-3-one, 92 Dimethylmagnesium, 86 Dimethylsulfonium methylide, 18, 113 Dioxane dibromide, 220... 

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