5a-Androstan-17-ol-3-one

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

In a 100-ml. round-bottomed flask equipped with a reflux condenser are placed 1.00 g. (0.0035 mole) of 5a-androstan-17/ -ol-3-one (Note 1), 0.90 g. (0.0048 mole) of tosylhydrazide (Note 2), and 70 ml. of methanol (Note 3). The mixture is heated under gentle reflux for 3 hours then cooled to room temperature. To the solution is added 2.5 g. (0.075 mole) of sodium borohydride in small portions during one hour (Note 4) and the resulting mixture is heated under reflux for an additional 8 hours. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ether, transferred to a separatory funnel, anil... 

Certain androstene derivatives are male sex hormones in higher animals (E 3.1). The most important ones in man are androstenedione and testosterone, which are produced in the testes. In the target tissues, e.g., the prostate gland testosterone is reduced to 5a-androstane-17 -ol-3-one, which seems to be the real metabolic effector. The androstenedione and testosterone that accumulate in certain plant cells, e.g., in the pollen of Pinus sylvestris probably have an ecological function (E 5.5.3). 5a-Androst-16-en-3-one and 5a-androst-16-en-3 x-ol are sex pheromones of the boar (E 4). 5oc-Androst-16-en-3-one is also a constituent of human urine (the urine of males containing three times the concentration of the urine of females) and 5a-androst-16-en-3oc-ol was shown to occur in the sweat of male humans. 

Fig. 7 Chemical structures of 5a-androstan-17(3-ol-3-one-2, 2, 4, 4-D4 (a) and 5a-androstan-17pl-ol-3-one-16, 16, 17-D3 (b) and schematic representation showing how deuterium-hydrogen exchange occurs during keto- and enol- form conversions (c)...

A soln. of 17a-methyl-5a-androstan-17y -ol-3-one in methanol satd. at 0-2° with NHg during 2 hrs., then hydroxylamine-O-sulfonic acid added portionwise during 10 min., and stirred 1 hr. at 0-10° crude 3,3-hydrazi-17a-methyl-5a-androstan-17/ -ol (Y 56%) dissolved with aq. 1 N Ag-nitrate in methanol, and aq. 2.5 N NaOH added with rapid stirring which is continued 0.5 hr. at room temp. -> 3,3-azo-17a-methyl-5a-androstan-17j -ol (Y 61-76%). F. e. s. R. F. R. Church, A. S. Kende, and M. J. Weiss, Am. Soc. 87, 2665 (1965). 

The phase-I-metabolism of testosterone leads primarily to 5a-androstan-17P-ol-3-one (dihydrotestosterone), 5a-androstan-3a-ol-17-one (androsterone), and 5P-androstan-3a-ol-17-one (etiocholanolone) (Fig. 3.6,2-4, respectively), which represent important parameters of the so-called urinary steroid profile in sports drug testing (see Chapter 6). 

Figure 4.5 Structures of selected steroidal analytes 5a-androstan-17P-ol-3-one (1), 5P-androstan-17P-ol-3-one (2), 17a-methyl-5a-androstan-17P-ol-3-one (3), la-methyl-5a-androstan-17P-ol-3-one (4), testosterone (5), nandrolone (6), 1-testosterone (7), metenolone (8), 5a-androst-l-ene-3,17-dione (9), metandienone (10), 18-nor-17P-hydroxymethyl,17a-methyl-androst-l,4,13-trien-3-one (metandienone metabolite) (11), androsta-4,6-dien-17P-ol-3-one (12), androsta-4,9-dien-17P-ol-3-one (13), trenbo-lone (14), methyltrienolone (15), tetrahydrogestrinone (THG, 16), and stanozolol (17).

Reduction of the A" -double bond with the rhodium complex is a very slow reaction, but it has been accomplished in 17)S-hydroxyandrost-4-en-3-one (140)d The product, 4a, 5a-d2-androstan-17j3-ol-3-one (141), is a further example of the preferential a-side deuteration in homogeneous solution as contrasted with the )S-face attack with heterogeneous catalysts. [For a more convenient preparation of compound (141) see section V-C.]... 

In 1965, Neumann and Wiechert [100] published the results of their investigations of some 150 steroids. They studied the androgenic and anabolic activity of steroids substituted in the C-1 and/or the C-2 position. Five parent compounds were chosen 1. 5a-androstan-17]3-ol 2. testosterone 3. 5a-dihydrotestosterone 4. A -5a-androsten-17j8-ol 3-one and 5. A -5a-androsten-17/3-ol. The parent compounds were further classified according to the substitution in the 17-position, i.e., l7j8-hydroxy, 17a-methyl 17j8-hydroxy, or 17/3-acetoxy compounds. 

A Androstadiene-17,8-ol-3-one, 1000 5i -Androstane-3,17-dione, 988 5a-Androstane-17t3-ol, 639 5a-Androstane-3a -ol-17-one, 988 Androstane-173-ol-3-one, 525 A -enol diacetate, 525... 

A solution of sodium borohydride (8 grams) in water (16 ml) was added to a stirred solution of 2(3,16(3-bis-piperidino-5a-androstan-3a-ol-17-one (17 grams) in tetrahydrofuran (70 ml) and methanol (30 ml) and the solution stirred at room temperature for 16 hours. The product was precipitated by the addition of water, filtered off, dried, and crystallized from acetone to give the diol (14.9 grams). 

The )reparation of 5a-androstan-17/9-ol from 5a-androstan-17/y-ol-3-one may be realized by classical methods such as the Wolff-Kishner or Clemm< ii.sen reduction. 

A solution of 2a,3a,16a,17a-diepoxy-17p-acetoxy-5a-androstane (25 grams), prepared from 3,17-diacetoxy-5a-androstane-2,16-diene (Chem. Abs. 1960, 54, 8908) by treatment with m-chlor-perbenzoic acid, in piperidine (120 ml) and water (40 ml) was boiled under reflux for 5 days, the solution was concentrated and the product precipitated by the addition of water. The solid was collected, dissolved in dilute hydrochloric acid, filtered to give a clear solution and precipitated by the addition of sodium hydroxide solution. Crystallization from acetone gave 2p,16p-bis-piperidino-5a-androstan-3a-ol-17-one (18.9 grams), MP 179-185°C. 

The combined action of lithium in liquid ammonia and carbon dioxide upon androst-4-en-3-one led to a synthesis of the /3-keto-ester (189), after esterification of the intermediate acid the reaction is one of reductive methoxycarbonyla-tion.82 Alkylation of the keto-ester (189) afforded a separable mixture of the 4/3-methyl steroid (190) as the major product (55%) and the corresponding 4a-methyl epimer. Reduction of the steroid (190) led to 4a-hydroxymethyl-4/3-methyl-5a-androstan-3/3-ol. Finally in this section, it has been noted that vinyl-magnesium bromide effects 1,4-addition to the a(3-unsaturated ketone 17/3-hydroxy-5a-androst-l-en-3-one to yield la-vinyl-5a-androstan-3-on-17/3-ol, which could be further reduced to the la-ethyl-3-ketone.83... 

The synthesis of the steroidal moiety of batrachotoxin (459) has been attempted. In a first pilot-reaction sequence, 5/ 0,19N-[ep(oxyethano-N-methylimino)]-androstan-17-ol (461) was prepared from 17)5,19-diacetoxyandrost-4-en-3-one (460) by a multi-step sequence. The technique developed in this model synthesis was then applied to build the C(14)-C(18) ring of 3)5,20( -diacetoxy-14)50,18AT-[ep(oxyethano-N-methylimino)]-5a,17a-pregnane (463) from the pregnane intermediate (462). This experience was used in the synthesis of 3-0-methyl-17a,20( -tetrahydrobatrachotoxinin A (472) (see Schemes 37 and 38). ... 

Ingenious application of remote oxidation has opened the way to a novel and potentially useful degradation of 5a-cholestan-3a-ol to 3a-hydroxy-5a-androstan-17-one ( androsterone ). The radical relay process, whereby photolysis of an iodoaryl ester with iodobenzene dichloride introduces a chlorine atom or unsaturation into the steroid nucleus, has been adapted by use of the 3a-(4 -iodobiphenyl-3-carboxylate) (301). The size of this ester grouping allows the iodine atom to come... 

Diaziridines and diazirines [1,483]. A Lederle group13 investigated the reaction of hydroxylamine-O-sulfonic acid with steroid ketones and found that only noncon-jugated 2(5a)-ketones and 3(5a or 5/3)-ketones react. A4-3-Ketosteroids, 17-keto-steroids, and 20-ketosteroids were found unreactive. A solution of 502 mg. of 17a-methyl-5a-androstane-17/3-ol-3-one (1) in methanol was saturated with ammonia at 2° and treated with 236 mg. of hydroxylamine-O-sulfonic acid, added in small portions. The diaziridine (2) was oxidized with silver oxide in ether in practically quantitative yield to the diazirine (3). 

Addition of diazomethane to ketosteroids. Alumina-catalyzed (Woelm, neutral, activity 1) reaction of diazomethane with 5a-androstane-17/3-ol-3-one (1) gives as the major product the epoxide (2).1 A minor product is probably a ring-enlarged... 

In contrast to the usual reaction of aromatic aldehydes with cyclic ketones o-nitrobenzaldehyde condenses with 17-ketones to produce good yields of seco-acids, a reaction which has been applied to the preparation of 16-oxa-steroids. Thus, 3 -hydroxy-5a-androstan-17-one or its acetate affords the seco-steroid (153), which can be oxidised either as the free acid by ozone and alkaline hydrogen peroxide to the diacid (155) or, as its methyl ester (154), with chromium trioxide to the monomethyl ester (156). Diborane reduction of the diacid (155) or lithium aluminium hydride reduction of the dimethyl ester (157) gave the trans-diol (158), cyclised with toluene-p-sulphonic acid to 16-oxa-androstan-3)5-ol (159) or, by oxidation with Jones reagent to the lactone (152) (as 3-ketone) in quantitative yield. This lactone could also be obtained by lithium borohydride reduction of the monomethyl ester (156), whilst diborane reduction of (156) and cyclisation of the resulting (151) afforded the isomeric lactone (150). The diacid (155) reacted with acetic anhydride to afford exclusively the cis-anhydride (161) which was reduced directly with lithium aluminium hydride to the cis-lactone (160) or, as its derived dimethyl ester (162) to the cis-diol (163) which cyclised to 16-oxa-14)5-androstan-3) -ol (164). 

As an example of a clear improvement in separation we can cite the data on the retention of steroids on a non-polar silicone stationary phase, SE-30, as presented by Heftmann [54]. Two monohydroxy-steroids, 5a-cholestan-3 3-ol and 5-cholesten-3 3-ol, have the same relative retention (2.85) on a column containing a non-polar stationary phase (internal standard cholestane), but the relative retentions of their trimethylsilyl derivatives are 2.60 and 2.55 and those of their chlorodichloroacetates are 3.79 and 3.62, respectively. The relative retention times of 3a-hydroxy-5a-androstan-17-one and 3j3-hydroxy-5a-androstan-17-one are similar at 0.96 and 1.00, respectively, whereas those of their TMS ethers are 0.46 and 0.61, respectively. 

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