5a-Cholestane

Fig. 1 Fluorescence scans of a blank (A) and of a mixture (B) of cholesterol (2), coprostanol (3), 4-cholesten-3-one (4), 5a-cholestan-3-one (5) and coprostanone (6), start (1), solvent front (7).

A recent study of the reduction of cholest-4-en-3-one with an excess of NaBH4 in 2-propanol shows that the corresponding cholest-4-en-3 -ol is the major product (44% yield) 4 other compounds (5a-cholestan-3a- and -3jS-ols, a sterol, possibly 5y -cholestan-3l -ol and an unidentified hydrocarbon) have also been isolated. When the reduction is carried out in the presence of ultraviolet light cholest-4-en-3/5-ol is still the major product (34%) but 7 other products are also obtained. These results show clearly the benefit of using Li[OC(CH3)3]3AlH for the preparation of the 4-en-3 -ol. ... 

The presence of an a-bromo substituent may cause anomalies. With NaBH4, 2a-bromo-5a-cholestan-3-one gives a mixture of epimers, in which the 3p-o predominates. 4 -Bromo-17)5-hydroxy-5)5-androstan-3-one acetate gives 25% of the 315,4 -bromohydrin and 34% of the 3a,4)5-compound. Reduction of 7a-bromo-3)5,5a-diacetoxycholestan-6-one gives exclusively 7a-bromocholestane-3)5,5a,6a-triol 3,5-diacetate,whereas reduc-... 

A solution of 0.2 g of cholestenone and 0.47 g of (< 3P)3RhCl in 150 ml of acetone is stirred under a hydrogen atmosphere for 3 days. The solvent is evaporated and the residue separated by thin layer chromatography to afford 5a-cholestan-3-one in 25-35% yield. ... 

This reaction sequence proceeds by cis addition of deuterium and the reduction products usually exhibit high isotopic purity. For example, 5a-cholest-2-ene (136), which is known to give a product of very unsatisfactory isotopic purity when deuterated with heterogeneous catalysts (see section V-A), gives 2<, 3 -d2-5a-cholestane (137) with better than 95% isotopic purity in homogeneous solution. ... 

The resulting product is purified by thin layer chromatography on silica gel in methylene dichloride yielding 8)S-di-5a-cholestane-3,6-dione (162) 13 mg, overall yield 26% mp 160-164°, which consists of 83% of dj-species. 

Deuterioboration of 5a-cholest-2-ene (171), followed by oxidation of the alkylborane intermediate with hydrogen peroxide in the presence of sodium hydroxide, illustrates the application of this method for the preparation of c/5-deuterium labeled alcohols.(For the preparation of tra 5 -deuterium labeled alcohols see section VII-A.) The predominant reaction product is 2a-di-5a-cholestan-3a-ol (172, 1.03 D/mole) which is accompanied by 3a-di-5a-cholestan-2a-ol (173) and other minor products." ... 

The successful labeling of the elusive 14a-position in cholestane represents a very important application of this reaction.It is known that hydroboration of the double bond in 5of-cholest-14-ene (174) occurs on the a-side. Consequently, by using deuteriodiborane (generated by the reaction of boron trifluoride etherate with lithium aluminum deuteride) and then propionic acid for hydrolysis of the alkylborane intermediate, 14a-d,-5a-cholestane (175) is obtained in 90% isotopic purity. This method also provides a facile route to the C-15 labeled analog (176) when the alkylborane derived from 5a-cholest-14-ene is hydrolyzed with propionic acid-OD. ... 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

A solution of 6a,7 x-oxido-5a-cholestan-3j8-ol acetate (232, 3.07 g) in anhydrous ether (100 ml) is treated with lithium aluminum deuteride (0.88 g) and... 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

The reaction of A -bromosuccinimide with 5a-cholestan-3-one enol acetate in aprotic conditions, described by Green and Long, is probably free radical in character cf. ref. 69). 

An illustration of the difference in reactivity of a-and / -halides is provided by the ready elimination of 1,4a-dibromo-5a-cholestan-3-one to 4a-bromo-5a-cholest-l-en-3-one in collidine at room temperature. Calcium carbonate in refluxing DMA is necessary to complete the dehydrobromination to the l,4-dien-3-one. ... 

Although an old method, the elimination of hydrogen halide from isolated halides is still occasionally recommended. An example is the formation of cholest-2-ene (108) from 3j5-chloro-5a-cholestane, followed by purification via the dibromide (ref. 185, p. 252). 

Such eliminations can usually be achieved under the conditions which work for sulfonates (e.g. bromides on alumina " ), and the anti-coplanar arrangement appears to be preferred. A large difference in reaction rate between the epimeric 3-chloro-5a-cholestanes has been observed in DMSO-potassium /-butoxide. ... 

The reduction of 2-a-halo-5a-cholestan-3-ones (142) is illustrative the yield rises with decreasing atomic number of the halogen, °°... 

---