5a-Cholest

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. ... 

Reduction of 5a-Cholest-2-ene with Deuterium and Tris-(tri-phenylphosphine)-chiororhodium... 

The rhodium catalyst (46 mg) is dissolved in acetone (10 ml) in a microhydrogenation apparatus which is then flushed three times with deuterium gas. After stirring the solution in an atmosphere of deuterium for about 1 hr the deuterium uptake ceases and constant pressure is attained. 5a-Cholest-2-ene (136, 19.5 mg) is added and the stirring continued until deuterium uptake ceases (about 3/4 hr). The solvent is evaporated to dryness and the residue is extracted with hexane and the resulting solution filtered through a small alumina column (3 g, activity 111). Evaporation of the hexane gives 2, 3 -d2-5oc-cholestane (137) 18 mg, 92% mp 78-79° isotope composition 94%d2,5%d, andl%do. ... 

While keeping the collected deuterioammonia at dry ice-isopropyl alcohol temperature, lithium wire (10 mg) is added, followed by a solution of 3/3-hydroxy-5a-cholest-7-en-6-one (161 50 mg) in anhydrous tetrahydrofuran (4 ml). The reaction mixture is stirred for 20 min, the cooling bath is then removed and the ammonia is allowed to boil under reflux for 40 min. A saturated solution of ammonium chloride in tetrahydrofuran is added dropwise until the deep blue color disappears and then the ammonia is allowed to evaporate. The residue is extracted with ether and the organic layer washed with dilute hydrochloric acid and sodium bicarbonate solution and then with water. Drying and evaporation of the solvent gives a semicrystalline residue which is dissolved in acetone and oxidized with 8 N chromic acid solution. After the usual workup the residue is dissolved in methanol containing sodium hydroxide (0.2 g) and heated under reflux for 1 hr to remove any deuterium introduced at C-5 or C-7. (For workup, see section II-B). 

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. ... 

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. ... 

Iodine isocyanate was used to synthesize the first steroidal aziridine, 2, 3 -iminocholestane (95). from 5a-cholest-2-ene (91). This reaction sequence which is believed to proceed through a three-membered ring iodonium ion (92) illustrates the limitation of pseudohalogen additions for the synthesis of -aziridines. The iodonium complex forms from the least hindered side (usually alpha) and is opened tmK5-diaxially to give a -oriented nitrogen function. The 3a-iodo-2 -isocyanate (93) is converted by treatment with... 

A solution of 5 g (14 mmoles) of 5a-cholest-2-ene in 100 ml ethyl acetate and 8 ml of 2.8 M (22 mmoles) cyanogen azide (CAUTION See Chapter 15 and ref. 139b) in ethyl acetate is heated at 50-53° for 24 hr, during which time about 22 mmoles of nitrogen is evolved. Solvent is removed by evaporation and the residue is applied in benzene to a column of 160 g of neutral alumina (activity grade III). Elution with petroleum ether-benzene (1 1) gives 1.6 g of... 

To a mixture of ethyl 5a-cholestan-3-one 2a-xanthate (2 g, 3.95 mmol) and 100 ml methanol is added sufficient ether to completely dissolve the solids. Sodium borohydride (90 mg, 2.36 mmol) is added directly to the reaction flask and the solution is stirred at room temperature for 4 hr. (The use of an excess of sodium borohydride and an extended reaction time produces 5oc-cholestan-2a,3a-thiirane.) The reaction is diluted with 200 ml ether and washed several times with ca. 100 ml water, dried (MgS04) and the solvent is removed under vacuum. The crude sticky gum is chromatographed on a column of 85 g silicic acid. The hexane eluates contain 5a-cholest-2-ene. Ethyl 5a-cholestan-3a-ol 2a-xanthate is obtained in ca. 30% yield by subsequent elution with benzene hexane (1 7) and the desired ethyl 5a-cholestan-3 -ol 2a-xanthate is eluted with ether hexane (1 3) in ca. 30% yield. 

The configurations assigned to (8) and (9) were established by comparison with the products resulting from epoxidation of 3-methyl-5a-cholest-2-ene followed by reduction with lithium aluminum hydride to the alcohol (9). The usual /ra 5-diaxial epoxide opening requires that the hydroxyl group, formed by reduction, is axial as shown in (9). 

The reaction of dichlorocarbenes with enol acetates has been studied by Stork and co-workers. ° This procedure was used to convert 3-acetoxy-5a-cholest-3-ene (31) into 4-chloro-A-homo-5a-cholest-4-en-3-one (33). 

Levisalles and co-workers have prepared A-homo-5a-cholestan-4-one by the dibromocarbene procedure starting with 3-methoxy-5a-cholest-2-ene. Wieland and Anner have converted 19-mesyloxy-A -3-keto steroids into... 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

Acetoxy-5a-chloro-6/3-hydroxyandro-stan-17-one, 278 3-Acetoxy-5a-cholest-3-ene, 364 3a-Acetoxycholest-4-ene, 4 3/3-Acetoxycholest-4-ene, 5 4a-Acetoxycholest-5-ene, 5 4/3-Acetoxycholest-5-ene, 5 3/3-Acetoxycholest-5-en-20a-ol, 71 3/3-Acetoxy-5,17-diketo-5,6-seco-androstan-6-oic acid, 435... 

An entirely different approach to specific dehydrogenation has been reported by. Breslow" and by J.E. Bald win.By means of this approach it was possible, for example, to convert 3ot-cholestanol (2) to 5a-cholest-14-en-3oc-ol (3), thus intro-... 

Because of the many examples of such activation of metal powders by TCS 14 only a limited and arbitrary number will be discussed here. The Clemmensen-type reduction of ketones such as cyclohexanone with Zn powder in the presence of TCS 14 affords, via 2082, 2084, and 2085, cyclohexene and, via 2082, O-silylated pinacol 2083 [19, 20]. Ketones such as 5a-cholestan-3-one 2086 are reduced by Zn dust-TCS 14 in TFIF, in ca 65-70% yield, to give 5a-cholest-2-ene 2087 and ca 5% 5a-cholest-3-ene [21] (Scheme 13.8). 

Sea cucumbers (Holothuroidea, Echinodermata) appear to be unique in their mode of squalene oxide (37) cyclization. Tritium-labeled lanosterol (33), cycloartenol (32) and parkeol (38) were individually administered to the sea cucumber Holothuria arenicola. While the former two triterpenes were not metabolized [22], parkeol was efficiently transformed into 14x-methyl-5a-cho-lest-9(l l)-en-3/ -ol (39) (Scheme 3). Other A1 sterols present in H. arenicola were not found to be radioactive and were thus assumed to be of dietary origin. The intermediacy of parkeol was confirmed by the feeding of labeled mevalonate (23) and squalene (26) to the sea cucumber Stichopus californicus [15]. Both precursors were transformed into parkeol, but not lanosterol nor cycloartenol, aqd to 4,14a-dimethyl-5a-cholest-9(ll)-en-3/J-ol (40) and 14a-methyl-5a-cholest-9(ll)-en-3/ -ol. Thus, while all other eukaryotes produce either cycloartenol or lanosterol, parkeol is the intermediate between triterpenes and the 14-methyl sterols in sea cucumbers. 

The pyrolytic method was first used to establish the chirality at sulfur in steroidal sulfoxide derivatives of 5a-cholestane (199). It was found that behavior of the diastereomeric sulfoxides 190, derivatives of 4/3-phenylsulfinyl-5a-cholestane having opposite configurations at sulfur, is quite different when the compounds are heated in boiling benzene. One of them, 190a, undergoes complete decomposition, affording 5a-cholest-3-ene 191, but the second diastereomer is quite inert under these conditions. 

At low temperatures RuO, as RuO /aq. Na(IO )/acetone/-70°C epoxidised some conjugated sterols. Thus 5a-cholesta-7,9(ll)-dien-3p-yl acetate (1), when so treated, gave 3p-acetoxy-9-oxo-9,ll-seco-5a-cholest-7-en-ll-al (2) together with three 8a,9a epoxysterols (3-5) (Fig. 3.1) [76, 77],... 

Oxidation of A, and A steroids using stoich. RuOyaq. acetone yielded cis-diols, dicarbonyls or carboxyhc acids thus 5a-cholest-2-en-3-ol 3-acetate gave... 

The reaction of 3/3-acetoxy-5a-cholest-8(14)-en-7-one with EtjAlCN was the key reaction in a synthesis of cholestanes containing an oxygenated 14a-substi-tuent. Cholest-4-en-3-one reacted smoothly with KCN-acetone cyanohydrin in benzene or acetonitrile containing 18-crown-6 to give the epimeric 5-cyano-cholestan-3-ones. An 11 -hydroxy-group increased the proportion of a-epox-ide produced in the reaction of 3-oxo-A -steroids with H202-0H . A 9a-fluorine substituent also influenced the stereochemistry of the reaction products and a... 

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