Isomerism of steroids

This reaction has been investigated extensively in D-ring isomerization of steroids [54] [55], Only a few examples are known in other systems. 

Type 3 This is an entirely different function in which certain forms of the GSTs catalyse the isomerization of steroids, thus ... 

E. Mincione. Thermal isomerization of steroid-boranes. IX. Synthesis of the steroidic B/C ring junction with the 8)3, 9)3 unnatural configuration. Ann. Chim. Rome), 1977, 67,119. 

Interestingly enough, both protons at C-11 are exchanged quite readily in 12-keto steroids. In these compounds C-11 is the only possible enolization site where the axial (/3) proton is probably expelled first. During ketonization, the deuteron attack is more likely to occur from the less hindered a-side. By this sequence the proton which was originally at the lla-equato-rial position becomes axial and readily available for expulsion in the next enolization step. Thus, isomerization of the C-11 hydrogens may be an important reason for the facile exchange at this position. (For a more detailed discussion of the mechanism of enolization and ketonization reactions, see ref 114.)... 

The intervention of mesoionic intermediates is suggested by the facile transformation of steroidal dienones, and by a number of acid-catalyzed nonphotolytic reactions which either parallel the photoisomerizations or correlate photoproducts from reactions in protic and aprotic solvents. The isomerization (175) -> (176) -l- (177) has also beeen achieved in the dark by acetic and formic acid catalysis and clearly involves the conjugate acid of the proposed mesoionic intermediate (199) in the dark reaction. Further,... 

Reversed micelles have also shown to be useful not only in bioconversions, but also in organic synthesis. Shield et al. (1986) have reviewed this subject and brought out its advantages in peptide synthesis, oxidation or reduction of steroids, selective oxidation of isomeric mixtures of aromatics, etc. In the oxidation of aromatic aldehydes to carboxylic acids with enzymes hosted in reverse micelles, the ortho substituted substrates react much more slowly than other isomers. 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

In contrast to the Johnson s D —> A-ring construction approach, Brown devised an A —> D-ring construction approach [22]. Starting from Wieland-Miescher ketone (30), a common source of the A, B-rings in the de novo synthesis of steroids, the C-ring was introduced via hydrazone allylation, ozonolysis, aldol condensation, and olefin isomerization (31 > 32). The D-ring was assembled by a reductive alkylation... 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

Dehennin L, Scholler R. 1973. Dienol heptafiuorobutyrates as derivatives for gas liquid chromatography of steroidal A -3-ketones determination of the structure of the isomeric dienol esters. Tetrahedron 29 1591-1594. 

Fig. 12. Relationship between configuration and the ease of the palladium-catalyzed isomerization of a double bond in the steroid nucleus.

The isomerization reaction is also encountered in chemical manipulations of steroids. Thus, many natural steroids contain a 5-en-3-ol combination of functionalities, e.g. cholesterol. Treatment of cholesterol with an oxidizing agent (aluminium isopropoxide is particularly suitable) leads to cholest -en-3-one, the tautomerism occurring spontaneously under the reaction conditions. 

In general the rates of hydrogenation of steroidal double bonds can be roughly classified as follows (a) readily hydrogenated A1, A2, A3, A4, A6, A14, A15 A14 16 diene, A16, A17(20), A20 and 19-vinyl (b) moderately difficult A5 > A22 and (c) difficult to hydrogenate A8 > A9(11) > A7 > A8(14). The data for the hydrogenation of A7-steroids is obscurred by the fact that this olefin is isomerized readily to the 8(14) position. Double bond isomerization does not occur with A7-9/ -steroids.18,23,39,54... 

The acid-catalysed isomerization of ,/ -epoxy ketones La the steroid field is further exemplified by the novel rearrangement show n in Eq. (485a), which wae investigated by Taub and co-workers,1 ... 

Another dwarf mutant of Arabidopsis, sax], defines a step upstream of DWF1 in the brassinosteroid biosynthesis pathway [27]. Rescue experiments with intermediates showed that saxl is involved in the oxidation and isomerization of 3P-hydroxyl,A5 6 precursors to 3-oxo-A4 5 steroids (Fig. (4)). 

During the reductive isomerization of 7/3-methyl- 14-isoestr-4-ene-3,17-dione 272 in HF SbF5/methylcyclopentane at 0°C, it was found879 that a 1,3-hydride shift occurs followed by kinetically controlled hydride transfer (Scheme 5.91). The mechanism of the reaction was confirmed by employing the deuteriated donor cyclohexane- as well as a specifically deuterium-labeled starting steroid. 

In [135, 136] the behavior of ketones of the steroid series in the Pfitzinger reaction was also studied. From dehydroepiandrosterone 139 and isatin 7 compound 140 was synthesized with a yield of 20%, and the reaction was accompanied by isomerization of the double bond [135], The reaction of estrone 141 and isatin 7 leads to the acid 142 [136],... 

The first such reaction published in 1908 by Ciamician and Silber was the light induced carvone —> carvonecamphor isomerization, corresponding to type b [1]. Between 1930 and 1960 some examples of photodimerizations (type c) of steroidal cyclohexenones and 3-alkylcyclohexenones were reported [2-5]. In 1964, Eaton and Cole accomplished the synthesis of cubane, wherein the key step is again a type b) photocycloisomerization [6]. The first examples of type a) reactions were the cyclopent-2-enone + cyclopentene photocycloaddition (Eaton, 1962) and then the photoaddition of cyclohex-2-enone to a variety of alkenes (Corey, 1964) [7,8]. Very soon thereafter the first reviews on photocycloaddition of a,(3-unsaturated ketones to alkenes appeared [9,10]. Finally, one early example of a type d) isomerization was communicated in 1981 [11]. This chapter will focus mainly on intermolecular enone + alkene cycloadditions, i.e., type a), reactions and also comprise some recent developments in the intramolecular, i.e., type b) cycloisomerizations. 

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