A4-Cholesten-3-one

Mauthner and Suida 2 isolated, as one of three neutral products resulting from the oxidation of cholesterol with aqueous chromic acid in acetic acid solution, the substance later identified as A4-cholesten-3,6-dione. The present procedure is based upon results of a reinvestigation of the oxidation by a low-temperature, non-aqueous procedure.3 

1 Department of Chemistry, Harvard University, Cambridge 38, Massachusetts. 

Submitted by Jerome F. Eastham and Roy Teranishi.1 Checked by James Cason, James Jiu, and Elmer J. Reist. 

To a 5-1. three-necked flask, equipped with a sealed mechanical stirrer, a dropping funnel, and a take-ofl reflux condenser, are added 2 1. of sulfur-free toluene and two boiling chips. The 

Commercial cholesterol, m.p. 146-149°, is satisfactory if dried at reduced pressure at 100° for 48 hours. The cyclohexanone is simply distilled before use, b.p. 153-155°. 

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Methods of preparation of A4-cholesten-3-one have been summarized in an earlier volume.3 The present modification is less laborious than the earlier method. 

The Oppenauer oxidation of cholesterol to A4-cholesten-3-one of m.p. 77-79° in 70-93% yield has been reported in these volumes.10 Isomerization of As-cholesten-3-one by a mineral acid or a base has been conducted satisfactorily only on a micro scale 6 the method of isomerization with oxalic acid has been reported.3... 

Inspection of Table 6.1 shows that the classical oxidation of sterols on the alcohol at the 3-position, using acetone as oxidant, works efficiently thanks to the migration of the alkene. Thus, the oxidation of cholesterol with acetone (E0 = 129 mV) must proceed via the thermodynamically disfavoured A5-cholesten-3-one (E0 = 153 mV) that evolves to the very stable A4-cholesten-3-one (E0 = 63 mV). In fact, acetone lacks oxidizing power for the obtention of many ketones as well as for the preparation of virtually all aldehydes. 

Preparation of enolphosphates. The reagent is used in ether solution to convert A4-cholestene-3-one (I) into the enol form for reaction with diethyl phosphoro-chloridatc and tricthylamine to give the phosphate ester (3). Reaction with lithium and ethylamine, and treatment with t-butyl alcohol then affords 5-methyl-A -coprostene (4). 

E. A4-Cholesten-3-one. A mixture of 100 g. of A5-cholesten-3-one (0.26 mole), 10 g. (0.11 mole) of anhydrous oxalic acid (Note 14), and 800 ml. of 95% ethanol is heated on the steam bath until all the solid is dissolved (15 minutes) and for 10 minutes longer, and then is allowed to stand at room temperature. If crystallization has not started after a period of several hours, the solution is seeded or scratched. After crystallization has proceeded at room temperature and then at 0-4°, the large, colorless, prismatic needles that separate are collected by suction filtration yield in the first crop 88-92 g., m.p. 81-82°, [a]o 92° chloroform... 

Isomerization of a,(i-unsaturated ketones and esters. Schering chemists57 observed that 6)S-bromo-A4-cholestene-3-one (1) on reductive debromination with zinc in aqueous ethanol is converted into A -choleslene-3-onc (2), but that some isomerization to the conjugated ketone occurs simultaneously. However, it was possible to obtain the noncortjugated ketone in 25% yield. The cross-conjugated ketone 6/8-bromo-A1,4-androstadiene-3,17-dione (3) was converted into A1,r,-androstadiene-3,17-dione (4). 

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. 

Chlorotrifluoromethylcarbene, 223 N-Chlorourethane, 60, 61 AM-Cholestadiene-3,6-dione, 60 5a-Cliolestane-3,6-dione, 60 5oCholestane-2a , 3a-oxide, 135 5CfrCholestane-2j3,3(3-oxide, 135 5(3-Cholestanone-3,6-dione, 60 A4-Cholestene-3,6-dione, 60, 65 Al-5/3-Cholestene-3,6-dione, 60 A4-Cholestene-3-one, 98 A4-Cholestene-4-one, 60 -Cholestene-a-epoxide, 116 A5-Cholestenone, 65 Cholesteryl acetate, 35, 171 Cholesteryl acetate dibromide, 40 Chromic acid, 54, 246 Chromic anhydride, 54-57, 150 Chromic anhydride-Acetic acid, 56 Chromic anhydride-Dimethylformamide, 56 Chromic anhydride-Pyridine complex,... 

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