5a-ANDROSTAN-3-ONE, 170-HYDROXY

The equatorial allylic alcohol 3)S-hydroxyandrost-4-ene is oxidised by Cr(Vl) 310 times faster than the saturated 3)3-hydroxy-5a-androstan-17-one, 5.7 times faster than the axial 3a-hydroxyandrost-4-ene and 6.9 times faster than its 3-deuterated analogue . The greater speed of oxidation of the equatorial isomer is in contrast to the pattern observed for saturated alcohols and probably arises from resonance between the double bond and the incipient carbonyl group. 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

The marked influence of solvent and temperature on product composition is illustrated by results obtained with 3 5-hydroxy-5a-androstan-17-one (5), which yields in addition to the 3a-fluoro derivative (6) the elimination... 

Vinyllithium Reaction169 To a cooled solution of 80 g of 3/ -hydroxy-5a-androstan-17-one in 1.5 liters of tetrahydrofuran is added 400 ml of 2 M 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-vinyI-5a-androstane-3j ,17jS-diol mp 205-207.5°. 

A solution of the 2p,3[3-epoxy-5a-androstan-17-one (30.0 g) in ethanol (130 ml), water (15 ml) and liquid ammonia was heated in an autoclave at 150°C for 6 h and the resultant crystalline suspension evaporated to dryness. Water (35 ml) and acetic acid (36 ml) were added and the solution kept at 90°C for 1 h, cooled and excess water added. The precipitated material was filtered off and the filtrate made alkaline with aqueous 10 N potassium hydroxide solution to precipitate a white solid which was filtered off, washed neutral with water, dissolved in methylene chloride, the solution dried (Na2S04) concentrated and ether added to give 2p-hydroxy-3a-amino-5a-androstan-17-one (14.3 g), melting point I92°-195°C. 

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 a good example, the cardenolides can be synthesized from 3/ -hydroxy-5a-androstan-17-one acetate and its 5-epimer by a four-step sequence76 (equation 50). 

Figure 7 Effect of derivatization on the 25eV El mass spectral fragmentation of 3 8-hydroxy-5a-androstan-17-one (top) TMS derivative (centre) methoxydimethylsllyl derivative showing more extensive fragmentation (bottom) fert-butyidimethylsilyl derivative with a large [M - 57]+ ion suitable for high-sensitivity monitoring.

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). 

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... 

The N-oxyl-4, 4 -dimethyloxazolidine derivative (685) of 17)3-hydroxy-5a-androstan-3-one 17-methylphosphonofluoridate has been used as a spin label... 

Syntheses of 2-hydroxy-3-amino-5a-androstan-17-ones and their regioisomers and their A -analogues have been reported. The 19-nor-A -1,2-epoxide (246) and isomeric A -4,5-epoxides (247) and (248) were synthesized in an essentially similar manner by epoxidation of the appropriate enone followed by dehydrogenation with Se02. 3-Hydroxy-9/3-oestra-l,3,5(10)-... 

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