Testosterone stereochemistry

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... 

Examples are shown in Fig. 23.9. Stereochemistry is indicated by dotted lines (a-bonds, behind the plane) and solid lines (P-bonds, in front of the plane) of any substituents on the rings. The sex hormones are the molecules mainly responsible for differentiating the sexes. The difference between testosterone and progesterone is a hydroxy versus an acetyl group. The natural sex hormones are used to treat prostate cancer, to alleviate menopausal distress, and to correct menstrual disorders. Other common natural steroids are estradiol, cholesterol, and cortisone. Infamous... 

In spite of all the successes of this structural work, the extraordinary discriminatory potential that chiroptical methods would obviously have if applied to the rather mundane task of preliminary routine screening for drugs has never been exploited. One reason for this may be that the sensitivity to stereochemistry has not been fully explained in theoretical terms. The utter inadequacy of the aforementioned theoretical models is easier to understand and appreciate when one realizes that the spatial redirection of just one bond in a molecule, while not affecting the absorption spectra for the structural analogs, will produce changes in the CD spectra that are so dramatic that their individual distinction is elementary. Outstanding illustrations are plentiful in the CD literature of the steroids, for example testosterone and its dihydro-derivative, Figure 1. 

The ease and the stereochemical course of hydrogenation of a,p-unsaturated ketones are particularly influenced by the nature of the solvent and the acidity or basicity of the reaction mixture. Some efforts have been made to rationalize the effect of the various parameters on the relative proportions of 1,2- to 1,4-addition, as well as on the stereochemistry of reduction. For example, the product distribution in -octalone hydrogenation in neutral media is related to the polarity of the solvent if the solvents are divided into aprotic and protic groups. The relative amount of cis- -decalone decreases steadily with decreasing dielectric constant in aprotic solvents, and increases with dielectric constant in protic solvents, as exemplified in Scheme 21 (dielectric constants of the solvents are indicated in parentheses). Similar results were observed in the hydrogenation of cholestenone and of testosterone. In polar aprotic solvents 1,4-addition predominates, whereas in a nonpolar aprotic solvent hydrogenation occurs mainly in the 1,2-addition mode. 

Androgens, the male sex hormones, proved far more elusive that either the estrogens and progestins since they occur at much lower concentrations in biological fluids. The bioassay used to track the isolation in this case comprised the capon unit . This was the amount of extract that produced a 20% increase in the surface of a rooster s comb. The 15 mg of pure crystalline testosterone isolated in 1931 came from about 15 0001 of urine. The structural investigations of this series relied on the then newly discovered side chain oxidations of cholestanol (13-1) (Scheme 1.13). This method in essence comprised fairly drastic oxidation of reduced cholesterols of known stereochemistry at the A-B junction to afford in fairly low yield products in which the side chain at Cn had been consumed to leave behind a carbonyl group. One of these products proved to be identical with androsterone (13-2). That compound had in turn been obtained from a sequence of reactions starting from dehydroepiandrosterone (13-3) that had been isolated from male urine. 

Oxidation of testosterone with osmium tetraoxide gives the corresponding 4,5-glycol (5-1) of undehned stereochemistry. By the method of formation, both hydroxyls probably have the same )8-conhguration. This product the undergoes spontaneous )8-dehydration to the enol hydroxide derivative formestane (5-2) (Scheme 5.5). 

The q -phenol complex undergoes conjugate addition at C4 with a variety of Michael acceptors (Fig. 7), including those with p substituents [44]. In most cases, the addition reaction is accomplished with an amine base as catalyst (see 25). Less reactive electrophiles, such as methyl acrylate or acrylonitrile, require a Lewis acid co-catalyst (e.g., 24). An example of the versatility of this reaction is shown in Fig. 7, where the aromatic steroid p-estradiol (26) is complexed (27) and subsequently alkylated exclusively at CIO (i.e.,para) at -40 °C. Since the osmium preferentially binds the a face of the steroid in 27, conjugate addition occurs from the p face, yielding the stereochemistry found in testosterone [26]. The overall yield of this transformation after decomplexation of the dienone product 29 is 69%. 

Fig. 4.4 Retention of stereochemistry in cytochrome P450-catalyzed carbon hydroxylations has been explicitly demonstrated with a variety of substrates, including octane (a), geraniol (b), and testosterone (c)...

Krauser JA, Guengerich FP (2005) Cytochrome P450 3A4-catalyzed testosterone 6P-hydroxyla1ion stereochemistry, kinetic deuterium isotope effects, and rate-limiting steps. J Biol Chem 280 19496 19506... 

Androstenedione is a steroid touted for its muscle-building ability through metabolic conversion to testosterone (page 456). What reaction must occur in the body to convert androstenedione to testosterone Why is the stereochemistry of this reaction important ... 

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