Epimerization ketones

Interesting syntheses of racemic sativene (203), copacamphene (205), cis-sativenediol (206), and helminthosporal (207) have been reported (Scheme 32). " The key step at the start of these syntheses is the acid-catalysed thermal rearrangement of (201), which is obtained by photolysis of piperitone in 1,1-dimethoxyethane, to give the two epimeric ketones (202). These two epimers are... 

This cyclization has obvious applications to the synthesis of steroids and indeed Johnson et al. applied this reaction to a synthesis of dZ-progcsterone. The key step in the synthesis involves the cyclization of (3) to give (4). This reaction was carried out with trifluoroacetic acid as above, but ethylene carbonate was added to the reaction to trap the vinyl cation. After cyclization potassium carbonate was added to hydrolyze the enol complex. In this way (3) was converted into (4) in 71 % yield. The tetracyclic ketone (4) was converted into progesterone (6) by ozonization followed by intramolecular aldol condensation. Nole that (4) is a 5 1 mixture of the 17/7- and 17a-epimeric ketones. The mixture was converted into (6) and then separated by fractional crystallization. 

It was originally believed that the dissolving metal reduction of cyclic ketones would invariably afford the more stable of a pair of epimeric ketones as the major product. Although it has since been established beyond reasonable doubt that these reactions are kinetically controlled and that the less stable epimeric alcohol frequently predominates, the belief persists that these reductions are under thermodynamic control. ... 

Other catalytic effects [1, 801-802, at end]. Treatment of a steroid 5a,6a-diol (1) with a trace of perchloric acid in refluxing dioxane results in rearrangement to the 5-epimeric ketones (2) and (3). On treatment with sodium ethoxide in ethanol. (3) is converted into (2), the point of equilibrium being 93% of the 5a-ketone and 7% of the 50-ketone. ... 

Desulphurization and reduction of 53 produced a mixture of epimeric ketones 54 and 54a which have been transformed into the thermodynamically more stable ketone 54 via sodium methoxide treatment. 

In connection with potential routes to sesquiterpenoids of the eremophilane and valencane classes, Marshall and Ruden have found that acid-catalysed cleavage of the cyclopropyl ketone (284) gives exclusively the enone (285). This is in contrast to the epimeric ketone (286) which yields predominantly (287). Leitereg has found that Robinson annelation of (-H )-dihydrocarvone with frans-3-penten-2-one gives as a major compound the bicyclic enone (288) which is isomeric with (-f- )-nootkatone (242). The full paper on the structures of a- (289) and j -rotunol (290) has been published. 

Reaction of 10 with 4-pentenyllithium gave 11. Enolization of 10 competed with imine addition and thus, recycling of this material was needed to achieve a respectable overall yield of 11 from ketone 9. Acid hydrolysis of 11 furnished enamine 12 after neutralization. An acid-mediated Mannich reaction converted 12 to a mixture of epimeric ketones 13. Oxidation of the 27-methyl group provided formamide 14. 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

In the early work on the synthesis of prostaglandins, zinc borohydride was used for the reduction of the 15-ketone function and a 1 1 mixture of epimeric 15(S)- and 15(/ )-alcohols was generally obtained. Subsequent studies led to reaction conditions for highly selective reduction to the desired 15(S)-alcohol. Some of the results are summarized in the following table. The most practical method is E which utilizes borane as the stoichiometric reductant and a chiral, enzyme-like catalyst which is shown. 

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. 

The reduction of an asymmetric cyclohexanone (e.g. a steroidal ketone) can lead to two epimeric alcohols. Usually one of these products predominates. The experimental results for the reduction of steroidal ketones with metal hydrides have been well summarized by Barton and are discussed in some detail in a later section (page 76) unhindered ketones are reduced by hydrides to give mainly equatorial alcohols hindered ketones (more accurately ketones for which axial approach of the reagent is hindered " ) are reduced to give mainly axial alcohols. 

By a suitable choice of conditions (metal hydrides or metal/ammonia) ketones at the 1-, 2-, 4-, 6-, 7-, 11-, 12- and 20-positions in 5a-H steroids can be reduced to give each of the possible epimeric alcohols in reasonable yield. Hov/ever, the 3- and 17-ketones are normally reduced to give predominantly their -(equatorial) alcohols. Use of an iridium complex as catalyst leads to a high yield of 3a-alcohol, but the 17a-ol still remains elusive by direct reduction. 

If the ketone function is adjacent to a hydrogen-bearing asymmetric center, the compound can undergo epimerization. In steroids with a normal skeletal configuration (8/3, 9a, 14a) there is no detectable epimerization at C-8 or C-9 during the exchange of and 11- ketones. 

The treatment of ketoximes with lithium aluminum hydride is usually a facile method for the conversion of ketones into primary amines, although in certain cases secondary amine side products are also obtained. Application of this reaction to steroidal ketoximes, by using lithium aluminum deuteride and anhydrous ether as solvent, leads to epimeric mixtures of monodeuterated primary amines the ratio of the epimers depends on the position of the oxime function. An illustrative example is the preparation of the 3(x-dj- and 3j5-di-aminoandrostane epimers (113 and 114, R = H) in isotopic purities equal to that of the reagent. 

The dehydration of -hydroxy ketones is a closely related reaction. In the case of 5,6-disubstituted 3-ketones, the 6-substituent usually remains in the less stable configuration. With acid catalyzed elimination, prolonged treatment or high concentration may cause epimerization ... 

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

The immediate product of opening of the a-epoxide (160) is the chlorohydrin (161) which slowly eliminates to give the olefin. In contrast, the epimeric chlorohydrin (165) formed from the jS-epoxide (164) eliminates spontaneously to give the same product (162). This difference is explicable by the known enolization preferences of 5oc- and 5/3-3-ketones. 

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

Reaction of the cisoid methoxymethylene ketone (36) with decomposing sodium chlorodifluoroacetate yields two epimeric adducts in 42 and 28 % yield, respectively, to which structure (37) has been assigned on the basis of NMR... 

The steric course of the alkylation of 17-ketones is not influenced by an 11-keto group. However, the presence of a 12a-OH group as well as a 16a-acetoxy group renders a-side approach to C-17 more difficult, and alkylation leads to epimeric mixtures. 

Oxidation of the hydroxy group in (10) to the ketone followed by isomerization affords the 10oc-methyl-A -3-ketone (11). In contrast, methylenation of 3)5-hydroxy-A ° -compounds proceeds in refluxing ether solution to give, after oxidation and acid rearrangement, the natural 10/5-methyl-A -3-keto steroids. With an epimeric mixture of 3fi- and 3a-A ° -alcohols only the )5-alcohol reacts under these imild conditions. ... 

The thermal reversal of the photochemical a-cleavage, i.e., the direct recombination of the resulting radical pair or diradical, can be recognized as such only when at least one of the a-atoms is chiral and is epimerized in the process. In fact, the frequently rather low quantum yields observed in the phototransformations of nonconjugated steroidal ketones may be largely due to the reversal of a-cleavage. 

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