A’-Cholesten-3-one

Muzart and coworkers investigated the CrOs/TBHP catalyzed oxidation of various benzylic methylenes and the allylic oxidation of A - and A -cholesten-3-one to the corresponding ketones in CH2Cl2 as well as benzotrifluoride (BTF) as solvent (Scheme 130) °. It could be shown that BTF in most cases improved the results even though the reactions were carried out with less TBHP than in CH2CI2 (4 eq. compared to 7 eq.). Yields in CH2CI2 varied from 21 to 94% and those in BTF from 40 to 99%. 

Oxidation of steroidal alketies. Mercuric acetate (2 eq.) reacts with A -steroids (I) to give as the major product A -15-ones (2) rather than the expected allylic acetates, 16(J-acetoxy-14-enes. The tetrasubstituted bond of A -cholestene is unreactive under the same conditions. A -Cholestene (disubstituted) reacts only slowly to give A -cholestene-3-one in 20 % yield with 70% recovery of the starting material. This unexpected reaction of steroidal trisubstiluted double bonds may proceed through an allylic acetoxylation followed by an oxidation step. 

The above ketone methylenation is applicable to highly hindered ketones, which are usually inert to the Wittig method. For example, a highly hindered tricyclic ketone (norzizanone, 4a) undergoes the methylenylation to give zizaene (4b equation 4). A -Cholesten-3-one (5a) was also converted to the nonconjugated diene 3-methylene-A -cholestene (5b equation 5). ... 

A Fannitalia group" reported, without details or yields, that both the a- and j3-epoxides derived from testosterone are rearranged by BFs-etherate in benzene to 4-hydroxy-A -3-ketones. Collins (Australia) made a more detailed study in the cholestane series and found that both the a- and the fi-oxide indeed give the hydroxy-A -cholestene-3-one but that they both yield a second product characterized as 5/8-A-norchoIestane-3-one. TTie latter compound evidently comes from an intermediate /3-keto aldehyde, probably by deformylation during chromatography on neutral alumina. 

Cupric nitrate-Pyridlne. This complex in the presence of triethylamine as base catalyzes the reaction of A -cholestene-3-one with molecular oxygen to form A -cholestene-3,6-dione. The yield is about twice that (4>tained by dichromateoxidation. ... 

Both simple carbonyl compounds and a,j8-unsaturated ketones react with this reagent with exclusive formation of epoxides (oxiranes), not cyclopropanes. Yields are as follows benzaldehyde, 75% cycloheptanone, 97% benzalacetophenone, 87% carvone, 89% eucarvone, 93% pulegone, 90% A -cholestene-3-one, 90%. 

Oxidation of A -cholestene-3-one in ether solution with 30% hydrogen peroxide and a catalytic amount of OSO4 gives both possible ei.s diols, which were isolated in the yields indicated. ... 

A -Cholestene-3-one (1) has a highly reactive methylene group and is oxidized by lead tetraacetate in benzene-acetic acid to give the 4a-acetoxy derivative (2)... 

Mild acid catalyst. A procedure for the preparation of A -cholestene-3-one (5) from cholesterol (1, unpurified) involves oxidation of the dibromide (2), debromination... 

In exploring, as a model case, the conversion of A -cholestene-3-one (3) into cholestane-3,6-dione (7), a Merck group" converted 750 mg. of the 3-ethyleneketal (4) into the 5a,6a-epoxide (5) by reaction with perbenzoic acid and treated a solution of (5) in tetrahydrofurane with 3 N aqueous perchloric acid solution at room temperature to effect hydrolysis of both the ethyleneketal group at Cd and the 5a,6o -epoxide group. Treatment of (6) with base effected dehydration and isomerization to the... 

The Ben May workers found that enol ethers also serve as intermediates. Thus the enol ethers of three 3-keto-5a-steroids on reaction with FCIO3 in pyridine at room temperature for 2 min., with subsequent acidification, afforded 2c -fluoro-3-ketones in yields of 75-90%. The enol ether of A -cholestene-3-one, namely 3-... 

In a synthesis of lanosterol from cholesterol, Woodward, Barton, et al found the most satisfactory method for introduction of the 4-gem-dimethyl group to be methylation of either or A -cholestene-3-one with methyl iodide and potassium t-butoxide in t-butanol. The method was later used in the synthesis Of resin acids. 

Chlorination of ketones. In some of the examples that follow, the reagent effects both oxidation and chlorination, as in the conversion of cholesterol into 6 3-chloro-A -cholestene-3-one (1) and in the oxidation-chlorination of the multifunctional... 

Seco-4-norcholestane-5-one-3-oic acid 5-oxime (3) on similar dehydration gives 4-hydroxy-4-aza-A -cholestene-3-one (4). 

For oxidation of testosterone to the dione it was found best to follow the procedure outlined in the formulation. Oxidation of cholesterol by a similar procedure afforded A -cholestene-3-one in 66% yield. 

Diels acid is high melting and sparingly soluble and can be isolated easily even though present in very small amounts. One of us oxidized cholesterol with sodium dichromate dihydrate in benzene-acetic acid and isolated the Diels acid in yield of 2.97% along with 6 neutral oxidation products. One of these, A -cholestene-3-one, might be but is not a precursor of the Diels acid. Cholesteryl acid chromate would seem to offer an attractive possibility for intramolecular attack of the allylic /3-hydrogen at C,. The active species in the hypobromite oxidation may be the hypobromite of cholesterol. 

A procedure developed by Mattox and Kendall for the liberation of cortisone acetate from the C3 2,4-dinitrophenylhydrazone utilizes a mixture of pyruvic acid, acetic acid, chloroform, and hydrogen bromide and affords the parent compound in 80% yield. For comparison. DePuy° prepared a mixture of 1 g. of A -cholestene-S-one 2,4-DNP with 100 ml. of chloroform and 100 ml. of the usual levulinic-hydrochloric acid and heated it under reflux for 3 hrs. Chromatography afforded pure A -cholestene-3-one in high yield. 

Oxidation of -3-ketosteroids. The reagent oxidizes A -cholestene-3-one to the aldehyde-lactone (3), possibly by formation and rearrangement of (2), an epoxide of an enol lactone. ... 

Johnson confirmed this finding and also prepared an identical complex from an equimolecular mixture of the components. They then treated the a-bromo-3-ketone (1) with tetramethylammonium acetate in refluxing acetone and obtained a mixture of acetoxyketones from which only 3a-acetoxycholestane-2-one (4) could be isolated in pure form. 2/3-Acetoxycholestane-3-one (5), the expected product, on treatment with the reagent is isomerized to (4). Treatment of 4a-bromocholestane-3-one with tetramethylammonium acetate in acetone (25°) gave A -cholestene-3-one (20%) and 4% of the complex of (3) and (4). 

Acetates of a-ketols or their vinylogs are subject to reductive elimination of the acetoxy group by treatment with zinc dust and acetic acid. Thus both 6a- and 6/3-acetoxy-A -cholestene-3-one (16) are reduced smoothly to A -cholestene-B-one (17) the free alcohols are reduced somewhat less smoothly." In the case of steroidal... 

The reduction of the tosylhydrazone of A -cholesten-3-one with catecholborane provides the best known route to A -5/3-cholestene (equation I). ... 

Cholestene, VIII, 285 Cholestenone, activity, IX, 243 dihydrocholesterol and, IX, 259 preparation of labeled, IX, 243 A Cholesten-3-one,... 

SCHEME 1.41 Synthesis of N-vinylpyirole from A -cholesten-3-one oxime and acetylene in the KOH/DMSO system. 

Decrease in the reaction temperature to 100 C and lower leads to deceleration of pyrrolization in comparison with rates of side processes, the most probable of which are prototropic isomerization of the bond in the initial ketoxime and partial deoximation. At 100°C (5 h), along with oxime of A -chloesten-3-one (isomer of A -cholesten-3-one), only traces of N-vinylpyrrolocholestene are detected in the reaction mixture OH NMR). When the temperature is raised above 120°C, a considerable amount of resin is formed that complicates isolation of the target pyrroles. 

---