A5 -Cholestene

The effects of OH and other groups become less pronounced when these groups are attached to carbons which are to the C=C double bond. The relative rates for 3-, 3,4-, and 3,7-substituted A5-cholestenes are given below.213 Oxygenation takes place exclusively on the a side of the A5-cholestenes, suggesting that the effect of the substituents is mainly electronic in nature. 

Muzart and coworkers investigated the CrOs/TBHP catalyzed oxidation of various benzylic methylenes447 and the allylic oxidation of A4- and A5-cholesten-3-one to the corresponding ketones in CH2CI2424 as well as benzotrifluoride (BTF) as solvent (Scheme 130)407. 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%. 

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. 

The oxidation procedure described affords a mixture of acids from which no component is easily isolable. When the oxidation is allowed to proceed in the temperature range 18-5° for 15-22 hours, as described in Note 1, isolation of the Diels acid (3,4-seco-A5-cholesten-3,4-dioic acid) is easily accomplished as follows. The carbonate extract is acidified and shaken with ether, and the clear aqueous layer is discarded. The ethereal solution, which may contain some suspended Diels acid, is not dried but is run into a flask and diluted with an equal volume of acetone. The mixture is evaporated to a volume of 15-20 ml. and cooled, and the Diels acid is collected as a white powder, m.p. 280-285° yield 0.5 g. 

D. A5-Cholesten-3-one. (Note 12.) The moist 5a,6/3-dibromo-cholestan-3-one from 150 g. of cholesterol is transferred to a 3-1. 

E. Ai-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]ff 92° chloroform... 

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. 

Chlorovinyl methyl ketone, 32,29 5-Chloro-2-vinylthiophene, 38, 89 3,4-j co-A5-Cholesten-3,4-dioic acid, 35, 38... 

Etherification. When cholesterol (1) is heated for several hours in dimethyl phosphite, cholesteryl methyl phosphite (2) is obtained as the main product. However, if /7-TsOH is present, 3/f-methoxy-A5-cholestene (3) is obtained as the main product in about 60 % yield. Cholestanol is converted by this method into 3/ -methoxycholestane in 60-70% yield. 

Use of diphenyl phosphite for etherification is limited to A5-3-hydroxysteroids (a homoallylic cation is probably involved in this case). Thus cholesterol is converted into 3/)-phenoxy-A5-cholestene in 50% yield by treatment with diphenyl phosphite in the presence of an acid catalyst. 

Alcohols iodides,1 Aliphatic primary and secondary alcohols react with (1) in THF, benzene, or hexane at 35-50° to give the corresponding iodides, usually in high yield. Even sterically hindered alcohols react, although in somewhat low yields. The reaction proceeds with inversion thus 3/J-cholestanol is converted into 3a-iodocholes-tane in 84% yield. Cholesterol is converted into the previously unknown 3a-iodo-A5-cholestene (40% yield). 

Complete retention of configuration is observed in the reaction of 3/i-ethoxy-A5-cholestene with acetyl chloride 3jJ-chloro-A5-choIestene is formed in high yield, accompanied by a small amount of A3 5-cholestadiene. 

The reaction has been used to convert A5-cholestenone-3 into 3-methylene-A5-cholestene in about 40% yield. Reaction of A5-cholestenone-3 with methylenetri-phenylphosphorane gives impure 3-methylene-A5-cholestene in < 15% yield. 

Details of the reaction of 3/ -acetoxy-A5-cholestene-7-one (2, 427) have been published.2... 

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 A5-cholesten-3-one by a mineral acid or a base has been conducted satisfactorily only on a micro scale 8 the method of isomerization with oxalic acid has been reported.8... 

The reaction was also employed for conversion of 5 -dihydroxycholestane into A5-cholestene-a-epoxide (80% yield). 

Meakins et al.1 state that perlauric acid is more suitable than perbenzoic acid for quantitative study of peroxidation of 3-substituted A5-cholestenes. The reagent converts lumisterol (1) into the 5/3,6/3-epoxide in 80% yield. 

The annulation of steroid skeleton with N-vinylpyrrole fragment is accomplished via the reaction of A5-cholesten-3-one oxime with acetylene under pressure in the system KOH/DMSO (120°C, 30 min. Scheme 1.41) [213]. The pyrrolization... 

The progesterone molecule combines almost exactly the structural fragments of pregnenolone and A5-cholesten-3-one (except for the position of the C=C bond). However, the results of interaction between progesterone dioxime and acetylene in... 

---