Reduction of Unsaturated Steroids

Reduction of Unsaturated Steroids.—A re-investigation of the hydrogenation of steroidal 4-en-3-ones has led to a major advance in understanding the factors controlling product stereochemistry, a long-debated problem. With a palladium catalyst, the sp 5a ratio of products is a function of the degree of occupation of the catalyst surface by hydrogen and by the steroid. Pre-equilibration of the catalyst with cholest-4-en-3-one afforded a 5j 5a ratio of 16 1, whereas the 

Syhora, J. A. Edwards, and A. D. Cross, Coll. Czech. Chem. Comm., 1969,34, 2459. 

4-en-3-one system, namely epoxidation, favouring the 4j ,5j3-epoxide, and hydrogen cyanide addition, which tends towards a 1 1 ratio of 5a- and 5 -cyano-ketones. A detailed investigation of stereochemical control in hydrogenation of the analogous octalone will also be of interest to steroid chemists. Discussion here is concerned mainly with competition between 1,2- and 1,4-addition of hydrogen, and with enolisation by added acids and bases. A detailed mechanistic interpretation is offered. 

Hydrogenation of 3,3-ethylenedioxy-5-enes (Pd-C) gives 5a-dihydro-deriva-tives in virtually quantitative yield, providing a convenient alternative to reduction with lithium-ammonia for the stereospecific conversion of 4-en-3-ones into 5a-3-ketones. 

Heterogeneous catalysis (Pd) in tritiation of l,4-dien-3-ones leads mainly to l) -tritiation (ca. 76%). Tritium distribution studies indicate that the reaction is probably a 1,4-addition of tritium onto the more exposed p-face of the dienone, which is tilted downwards with respect to ring b (211). Homogeneous catalysis with tris(triphenylphosphine)rhodium chloride, however, is known to favour la-tritiation. Similarly, homogeneous hydrogenation of the less reactive 

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Reduction of Unsaturated Steroids.— Twenty-five steroidal 4-en-3-ones,... 

Electrophilic Addition Other Addition Reactions Reduction of Unsaturated Steroids Oxidation and Dehydrogenation Miscellaneous Reactions... 

Reduction of Unsaturated Steroids.—Reduction with di-imide [provided by hydrazine hydrate and copper(ii) acetate in methanol] provides a novel and stereospecific conversion of steroidal 4-en-3)5-ols into 5a-dihydro-compounds. By contrast, catalytic hydrogenation is non-stereospecific and is often accompanied by partial hydrogenolysis, so the new method offers considerable promise. Catalytic reduction of 3jS-hydroxyandrost-4-en-17-one with tritium and a Pt catalyst gave 3)5-hydroxy-5a-androstan-17-one with the tritium distribution 4a, 37% 5a, 43% and 6a, 20%. The 5jS-isomer was also formed, with tritium at 4, 29 % 5, 54 % 6, 4.7 %, and 6a, 13 %. Tritium analysis was achieved by a combination of equilibration with base, bromination-dehydrobromination, and dehydrogenation. The appearance of tritium at C-6 indicates olefinic bond migration in contact with the catalyst. ... 

The results of the reductions of some steroidal a,)3-unsaturated ketones have been summarized by Brown. " The carbonyl group is usually reduced to the hydrocarbon, but the behavior of the double bond depends on the structure of the compound undergoing the reduction. Cholest-4-en-3-one gives chol-est-4-ene. Addition of aluminum chloride to a solution of a 4-ene-3,6-dione followed by treatment with LiAIH4 gives the 4-ene-6-one. Steroid 4,6-dien-3-ones yield mixtures of dienes. When the ketone and double bond are in different rings the results become even more complex dienes as well as mono-enes are obtained. 

The main methods of reducing ketones to alcohols are (a) use of complex metal hydrides (b) use of alkali metals in alcohols or liquid ammonia or amines 221 (c) catalytic hydrogenation 14,217 (d) Meerwein-Ponndorf reduction.169,249 The reduction of organic compounds by complex metal hydrides, first reported in 1947,174 is a widely used technique. This chapter reviews first the main metal hydride reagents, their reactivities towards various functional groups and the conditions under which they are used to reduce ketones. The reduction of ketones by hydrides is then discussed under the headings of mechanism and stereochemistry, reduction of unsaturated ketones, and stereochemistry and selectivity of reduction of steroidal ketones. Finally reductions with the mixed hydride reagent of lithium aluminum hydride and aluminum chloride, with diborane and with iridium complexes, are briefly described. 

Steroid hormones are generally converted into inactive metaboic excretion products in the liver. Reactions include reduction of unsaturated bonds and the introduction of additional hydroxyl groups. The) resulting structures are made more soluble by conjugation with curonic acid or sulfate (from PAPS, see p. 160). Approximate ) twenty to thirty percent of these metabolites are secreted into the bile and then excreted in the feces, whereas the remainder ae t released into the blood and filtered from the plasma in the kidney, passing into the urine. These conjugated metabolites are fairb1 water-soluble and do not need protein carriers. 

Steroidal n-alfylpalladium complexes. These complexes of unsaturated steroids are prepared conveniently by reaction in chloroform or acetone with this Pd(II) complex. Ergosterol (1) is converted in this way into the dimeric complex 2, with loss of the hydroxyl group. Two interesting new reactions of the complex 2 are reported reduction (o a triene (3) and oxidation to a tricnol (4). 

The combined action of lithium in liquid ammonia and carbon dioxide upon androst-4-en-3-one led to a synthesis of the /3-keto-ester (189), after esterification of the intermediate acid the reaction is one of reductive methoxycarbonyla-tion.82 Alkylation of the keto-ester (189) afforded a separable mixture of the 4/3-methyl steroid (190) as the major product (55%) and the corresponding 4a-methyl epimer. Reduction of the steroid (190) led to 4a-hydroxymethyl-4/3-methyl-5a-androstan-3/3-ol. Finally in this section, it has been noted that vinyl-magnesium bromide effects 1,4-addition to the a(3-unsaturated ketone 17/3-hydroxy-5a-androst-l-en-3-one to yield la-vinyl-5a-androstan-3-on-17/3-ol, which could be further reduced to the la-ethyl-3-ketone.83... 

Polarographic reduction of unsaturated 3-, 7-, and 20-oxo-steroids in aqueous DMF has been studied. The ease of reduction increases with extended conjuga-... 

Treatment of dehydroepiandrosterone (13-3) with phosphorus pentachloride replaces the hydroxyl at position 3 with retention of configuration (13-4). It had been established prior to this work that catalytic reduction of unsaturation in steroids proceeds almost invariably from the bottom side to afford reaction products as their 5a epimers, as for example... 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16). Catalytic reduction... 

In the context of diagenesis in recent anoxic sediments, reduced carotenoids, steroids, and hopanoids have been identified, and it has been suggested that reduction by sulhde, produced for example, by the reduction of sulfate could play an important part (Hebting et al. 2006). The partial reduction of carotenoids by sulfide has been observed as a result of the addition of sulfide to selected allylic double bonds, followed by reductive desulfurization. This is supported by the finding that the thiol in allylic thiols could be reductively removed by sulhde to produce unsaturated products from free-radical reactions (Hebting et al. 2003). 

An unusual reaction was been observed in the reaction of old yellow enzyme with a,(3-unsat-urated ketones. A dismutation took place under aerobic or anaerobic conditions, with the formation from cyclohex-l-keto-2-ene of the corresponding phenol and cyclohexanone, and an analogous reaction from representative cyclodec-3-keto-4-enes—putatively by hydride-ion transfer (Vaz et al. 1995). Reduction of the double bond in a,p-unsaturated ketones has been observed, and the enone reductases from Saccharomyces cerevisiae have been purified and characterized. They are able to carry out reduction of the C=C bonds in aliphatic aldehydes and ketones, and ring double bonds in cyclohexenones (Wanner and Tressel 1998). Reductions of steroid l,4-diene-3-ones can be mediated by the related old yellow enzyme and pentaerythritol tetranitrate reductase, for example, androsta-A -3,17-dione to androsta-A -3,17-dione (Vaz etal. 1995) and prednisone to pregna-A -17a, 20-diol-3,ll,20-trione (Barna et al. 2001) respectively. 

Hadler 26) employed conformational analysis to explain the difference in the proportion of cholestane to coprostane derivatives resulting from the reduction of A and d steroids. He suggested that the hydrogenation process involved the formation of a quasi-ring structure between the unsaturated carbon atoms and two hydrogens originally dissolved in the metal, a mechanism which is similar to one proposed by Beeck (27) and by Jenkins and Rideal 28). He assumed, in effect, that the saturated struc-... 

The reduction of a,/ -unsaturated ketones, e.g., 7, by lithium in ammonia is another possibility for generation of enolates19. This method has been mainly used in the preparation of enolates for stereo- and regioselective alkylations in the steroid and terpenoid fields (see... 

Co(III)] complexes. For example, the coupling of 3-halocholestanes (333) and Michael acceptors affords epimeric mixtures of the 3-homologated steroids (334). The electrochemical nucleophilic acylation of a, 3-unsaturated aldehydes, a,3-unsaturated ketones and a,(3-unsaturated nitriles with acyl anhydrides affords adducts (335) in moderate yields.226a-b Similarly, the reduction of N-methyloxazolinium salts (336) affords die A, O-acetal intermediates (337) which are readily hydrolyzed (Scheme 102).226c... 

Chlorotrimethylsilane with zinc in THF reduces 3-oxo-5 a-steroids directly to A2-olefinic derivatives, but most other oxo-groups are unreactive, allowing selective attack on the 3-oxo-group in diones.178 The 5)8-steroidal iminium perchlorate (204), obtained179 by reduction of the A4-unsaturated analogue with the Hantzsch ester (a dihydropyridine), can be reduced further with the same reagent to give the 3/3-pyrrolidinium salt (205) stereospecifically.180... 

Reduction of saturated l-oximino-5a-steroids with usual reagents gives the la-amino-derivatives. The previously unknown 1/3-amino-compounds have now been obtained by reduction of the A2-unsaturated 1-oxime. Hydrogenation (Pt-H2) leads to the saturated la- and 1/3-amines directly, while zinc-acetic acid gave the unsaturated amines which could be hydrogenated in a separate step to give the saturated amines.197 The four isomeric 16-azido-17-alcohols, and thence the 16-amino-17-alcohols, have been prepared by the routes indicated in Scheme 8 [3-methoxyoestra-l,3,5(10)-triene series]. The 16/3,17/3-epoxide gave a mixture of two tra/ts-azido-alcohols.198... 

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