A-enolation

The 20-ketone of an 11,20-dione has been protected as a A -enol acetate while the 11-ketone is reduced with NaBH4 in aqueous tetrahydrofuran for 9 days at room temperature. The presence of the 17(20)-double bond made possible the later introduction of a 17a-substituent. " r... 

In general bromination of 20-ketones is directed to the introduction of functionality at C-21. However, on occasion 17-bromo compounds are required for dehydrobromination to A -20-ketones, although these are generally obtained in other ways. Kinetic enolization of a 20-ketone gives the A °-enol, whereas the thermodynamic product is the A kjsomer. An interesting enolate trapping reaction has been used recently to prepare 16-methyl-A -20-ketones ... 

The selectivity is probably impaired by bromination at C-2 and C-9. Bromination under buffered conditions of the A -enol acetate prepared from acetic anhydride with perchloric acid catalysis may give better results. See also ref. 55 for a similar bromination. 

This dehydrogenation of A -3-ols to A -3-ketones undoubtedly proceeds through the A -3-ketone and the A -enol. The reaction has also been carried out using chloranil and yields of up to 75 % have been claimed.(See next section for a discussion of mechanism.)... 

Agnello and Laubach suggested that the dehydrogenation of A" -3-ketones to A -3-ketones by chloranil proceeds through the A -enol, which suffers hydride loss from C-7. The failure of 7a-methyl-A -3-ketones to undergo dehydrogenation while the 7/5-isomers do so readily indicates that specific removal of the 7a (axial) hydrogen probably occurs in unsubstituted compounds. ... 

An explanation for the difference in behavior of chloranil and DDQ towards A -3-ketones was first provided by Ringold and Turner. The A -enol (67) is produced faster than the more stable A -enol (68) but is not attacked appreciably by chloranil, which lacks sufficient oxidizing potential. Instead, the more easily oxidized A -enol (68) is dehydrogenated to (69) as it is produced. With DDQ, the faster formed A -enol (67) can be effectively dehydrogenated and the A -3-ketone (70) is formed ... 

The use of A -enol ethers as substrates for dehydrogenation is often attractive. Aqueous acetone at room temperature gives yields ranging from 70 to 88% other systems with acid catalysis have also been used, e.g. ... 

Another route to 5a compounds (57) proceeds from the dienol ether (58) by selective catalytic hydrogenation of the A -double bond with concomitant shift of the 3,4-double bond to the 2,3-position. If the hydrogenation is carried out in the presence of traces of base, double bond migration is suppressed and the difficultly accessible A -enol ethers of 5a-series (59) are thus obtained. 

Unsubstituted 20-ketones readily form enol acetates. Reaction with isopropenyl acetate yields the kinetic A -isomer (86, R = CH3CO) which is equilibrated to the A -enol acetate (85, R = CH3CO) on exposure to acetic anhydride-/7-toluenesulfonic acid. Treatment of the 20-ketone according to the latter conditions gives the A -enol acetate directly. 

A ( )-Enol-l 1-acetates are formed by distillation of acetic anhydride in the presence of / -toluenesulphonic acid. Another procedure employed for the synthesis of enol benzoates involves treatment with benzoic anhydride and triphenyl methyl sodium or ethynyl sodium. Suitable procedures utilizing a diluent have been developed for the enol esterification of a 20-ketone without affecting an 11-ketone. 

The enamines, enol ethers and enol acetates of A -3-keto steroids provide important substrates for fluorination with FCIO3. Reaction of such A -enol ethers and acetates (6) with perchloryl fluoride results in 6a- and 6jff-fluoro-A -3-ketones (7) and (8), the latter representing the more abundant isomer. Tetrahydrofuran or dioxane-water mixtures appear to be particu-... 

It is possible to change the stereochemical result of the alkylation by replacing the 3-ketal protecting group with a A -enol ether. This structural change eliminates a severe 1,3-diaxial interaction to a-face methylation and results in the formation of the 5a-methyl steroid (15) in about 35% yield, ... 

The preparation of 17j -hydroxy-4a-methyl-5a-androstan-3-one (3) which cannot be obtained by direct alkylation or via formyl or oxalyl ketones was achieved by Schaub in 40% yield by the Stork " alkylation procedure. As discussed in the introduction this method proceeds by trapping the A -enolate (2), obtained from (1) and lithium in liquid ammonia, with methyl iodide. 

A method of fixing the position of the double bond involves first condensing the 20-ketopregnane with benzaldehyde at C-21, then reducing the ketone to hydroxyl and dehydrating.Alternatively, the 20-keto-21-benzylidene steroid can be converted to the A ° -enol chloride prior to ozonolysis. 

Three possible mechanisms for the Serini reaction were originally suggested. These proceed via (a) a A -enol acetate, (b) a A -epoxide, or (c) a cyclic orthoester ... 

One of the most widely used methods for the introduction of a 17a-hydroxy group into a 20-ketopregnane is via A ° -enol acetate formation. The overall reaction is ... 

Epoxidation of the A -enol acetate was originally carried out with per-benzoic acid. Monoperphthalic acid has also been used, but is apparently more susceptible to steric and conformational factors. The commercially available peracetic acid is generally most convenient. Based on the expected backside attack, the derived epoxides have the 17a configuration, and hydrolysis always produces the 17a-hydroxy group. 

Ketopregnanes are readily converted to their A -enol acetates with... 

The reaction of A -iodosuccinimide with a A ° -enol acetate described earlier can also be applied (with the same excellent yields) to the A -ana-logs ... 

The (/ ,/ )-A, 7V -bis[3,5-bis(trifluoromethyl)phcnylsulfonyl]-l.2-dipheny]-l,2-ethanediaminc also furnishes <7 t/-/(-hydroxy esters with high induced stereoselectivity64. For this purpose, the bromide generated from 10 and tribromoborane is reacted with tm-butyl propanoate in the presence of triethylamine to deliver the (A )-enolate. The subsequent addition to aldehydes gives predominantly tOT/ -/)-hydroxy esters (anti/syn 94 6 to 99 1) of 75 to 97 % ee. The diastereose-lectivity can be improved when, instead of /erf-butyl propionate, the corresponding ( + )-men-thyl ester is used64. 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

Derivatives with various substituted sulfonamides have been developed and used to form enolates from esters and thioesters.137 An additional feature of this chiral auxiliary is the ability to select for syn or anti products, depending upon choice of reagents and reaction conditions. The reactions proceed through an acyclic TS, and diastereoselectivity is determined by whether the E- or Z-enolate is formed.138 /-Butyl esters give A-enolates and anti adducts, whereas phenylthiol esters give syn adducts.136... 

A. Enolic Dienes Derived from Testosterone-17/J-acetate. 499... 

The aldol reaction has been known for over a century. Though largely attributed to Wilrtz, the first aldol reaction was reported several years earlier by Borodin.81 813 Stimulated by the observation that (Z)- and (A)-enolates react stereospecifically to provide syn- and //////-aldol addition products, several catalytic systems for aldol addition... 

On the other hand, the formation of the perhydrophenanthrene system instead of the linear anthracene system is favored by the fact that cjs-decalones form almost exclusively the A -enolate (according to the conventional numbering of decalins) and consequently alkylation takes place selectively at C(10) instead of C(6) (according to the conventional numbering of steroidal systems). 

Notice that although the A -enol is favoured over the A -enol in c -decalin systems [8], the resulting product from the corresponding Mannich condensation would lead to a highly congested compound with two 1,3-diaxial interactions instead of only one 1,3-diaxial interaction in luciduline. 

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