Cholestenes, addition

Reduction of 3-Nitro-2-cholestene. - Zinc dust (dOOmg) was added in portions during 1 hr to a stirred warm (4(fC) suspension of 250 mg of 3-nitro-2-cholestene in 15mL of acetic acid and 0.5 ml of water. After 4 hr reflux, the mixture was Altered hot and the zinc washed well with hot HOAc. Addition of water and extraction with ether gave 116mg of product."... 

More recently, reports by Quayle and co-workers, have shown that benzylated 2-chloroglucal derivatives can be lithiated, with. vec-butyllithium in THF at -78 °C, and the ensuing lithiated species trapped with a variety of carbon electrophiles that include enolizable carbonyl derivatives.25 4-Cholesten-2-one underwent 1,2-addition to yield a 5 1 mixture... 

This latter point was experimentally proved by converting A5-cholesten-3-one into the conjugated A4 isomer in the presence of CU/AI2O3. The subsequent hydrogen addition to the A4-3-one follows the stereochemistry expected in the presence of heterogeneous catalysts as CU/AI2O3 which produces an excess of the 5p isomer also with gaseous H2. 

Iodine azide adds stereo- and regio-specifically to 2-cholestene giving a frans-diaxial adduct with azide at the 2-position, a consequence of attack by I from the less hindered face of the steroid. With 1-hexene the addition proceeds regiospecifically to yield the secondary azide, most likely via a three-mem-bered iodonium ion intermediate.111 With (Z)-2-octene, BrN3 addition gives a single adduct in 71% yield... 

Other steroid systems have also been investigated. Methyl groups at the bridgehead position always shield the /3-side and thus promote exclusive a-attack. Additionally, for the triacetoxy derivative 1268, an intermediate in the synthesis of a-ecdysone, and for 3j6-acetoxy-8(14)-cholesten-6-one (14)69, the regioselectivity of the ene reaction with singlet oxygen is high. In both cases only the y-hydroperoxy-a,/J-unsaturated ketone is formed. 

This is surprising, since the reaction of dinitrogen tetroxide with (E)-, 2-diphenylethylene in diethyl ether produced a 3 2 mixture of diastereomeric l,2-dinitro-l,2-diphenylethanes134 The reaction of 2-cholestene with dinitrogen tetroxide/iodine afforded 2/ -iodo-3a-nitro-5oi-chole-stane, this was also the product obtained by the addition of nitryl iodide (see previous section). 

The addition to steroidal alkenes promoted by chromium(II) chloride77 78, as well as thermal and photolytic additions, are predominantly trans 0. 2-Cholestene underwent thermal addition of ethyl dichlorocarbamate to give 2j8-chloro-3a-ethoxycarbonylaminocholestane80. Low yields of adducts were obtained from 3j8-acetoxy-5-androsten-17-one80. 

The synthesis of fluorosteroids4,7,27,28,41 43,45 by the addition of hydrogen fluoride to pregnenc and cholestene derivatives is governed by stereochemistry and by the nature of substituent groups.7,27,28 For example, the formation of 5a-fluoro derivative 6.27... 

To a solution of 5.50 g (14.2 mmol) of 3-cholestanone in 125 mL of ethyl acetate is added 3.30 g (17.2 mmol) of benzeneselenyl chloride (CsHsSeCl), and the red-orange solution is stirred for 1 h until it turns pale yellow. Water (25 mL) is added to the stirred mixture, the aqueous layer is drained, and to the organic phase is added 55 mL of tetrahydrofuran and, dropwise, 3.5 mL (34.3 mmol) of 30% hydrogen peroxide while the mixture is stirred for an additional hour at a temperature below 35 °C. The reaction mixture is washed with water and a solution of sodium carbonate, dried, and evaporated to give 5,25 g (96%) of crude product, which on recrystallization from ethanol furnishes 2.43 g (45%) of l-cholesten-3-one, mp 95-97 °C. 

This reaction has been utilized in the synthesis of azidosteroids ". Addition to 2-cholestene (224) occurs regioselectively and adducts 225 and 226 have been isolated in 37% and 27% yield respectively. By comparison, ionic addition leads to the /ranj-diaxial product (227). Such differing orientations of the products obtained from homolytic and heterolytic addition may be synthetically valuable. 

Olefin addition. Addition of iodine and A -cholestene to a solution of silver trifluoroacetate in methylene chloride generates iodine trifluoroacetate which adds to the olefin to give 3a-iodo-2 -trifluoroacetatoxycholestane in 72% yield. Lithium aluminum hydride effects reduction and deacetylation to cholestane-2/3-ol. D. E. Janssen and C. V. Wilson, Org. Syn., Coll. Vol., 4,547 (1963)... 

The sequence can also be applied to the enolate anion formed by conjugate addition of organometallic reagents to a,/8-unsaturated ketones. Thus addition of diethyl phosphorochloridate to a mixture of A4-cholestene-3-one (4) and dimethyl-copperlithium gives the diethyl enol phosphate (5) in 55% yield. Reduction of the ester gives the olefin (6) in high yield. 

The microsomal 26-hydroxylase in rat liver has a higher substrate specificity than the mitochondrial. Of a number of C27-steroids, only 5j8-cholestane-3a,7a,12a-triol, 5)8-cholestane-3a,7a-diol, 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one were 26-hydroxylated to a significant extent [126]. In addition to hydroxylation in the 26 position, 5)8-cholestane-3a,7a,12a-triol was hydroxylated by the microsomal fraction of rat liver in the 23, 24 , 24/8 and 25 positions [40]. The hydroxylation in the 25 position was about as efficient as that in the 26 position. 

In the microsomal 5 a saturation of the double bond in 7a-hydroxy-4-cholesten-3-one there is a stereospecific transfer of a hydride ion from the 4B position of NADPH to the 5 a position of the steroid [169]. From the results of experiments on the stereochemistry of the addition of the proton to the 4 position, it was concluded that the reduction of the double bond is likely to involve a non-stereospecific addition of hydrogens or a cis addition rather than a trans addition. 

Ketenes add to the least hindered face of an alkene preferentially. Selective addition to one face of a cycloalkene is often observed. Addition of dichloroketene to 2-cholestene gives >80% of the cyclobutanone shown. 

---