Dehydroepiandrosterone oxidation

Hydrolysis of the acetate (71) followed by Oppenauer oxidation gives B-norcholest-4-en-3-one in high yield. An analogous reaction sequence can be used to prepare B-norprogesterone and derivatives of B-nortestosterone from pregnenolone acetate and dehydroepiandrosterone acetate, respectively."" ... 

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450cl7) that catalyzes 17tt-hydroxylation. This is therefore a dual function protein. The lyase activity is important in both the adrenals and... 

Brown RC, Cascio C, Papadopoulos V. 2000. Pathways of neurosteroid biosynthesis in cell lines from human brain regulation of dehydroepiandrosterone formation by oxidative stress and beta-amyloid peptide. J Neurochem 74 ... 

An exactly analogous enzymic transformation is encountered during the formation of oestrogen and androgen sex hormones, e.g. estradiol and testosterone respectively, where dehydroepiandrosterone is oxidized to androstenedione. 

Considering the excellent chemoselectivity observed in the allylic oxidation of dehydroepiandrosterone (Scheme 16), it was interesting to evaluate the selective allylic alcohol oxidation in the presence of a secondary saturated hydroxyl group using the BiCls/f-BuOOH system. This study was performed using androst-... 

Reactions catalyzed by 11 (3-hydroxysteroid and 17(3-hydroxysteroid dehydrogenases, (a) 11 (3-hydroxysteroid dehydrogenase type 1, an NADPH-dependent enzyme, catalyzes the conversion of the inactive steroid, cortisone, to cortisol, which is the biologically active glucocorticoid. 11 (3-hydroxysteroid dehydrogenase type 2, an NAD+-dependent enzyme, catalyzes the reverse direction, (b) 17(3-hydroxysteroid dehy-drogenase type 1, an NADPH-dependent enzyme, catalyzes the reduction of estrone to estradiol. Type 2, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone. Type 3, an NADPH-dependent enzyme, catalyzes the reduction of androstene dione to testosterone. Type 4, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone, and androstenediol to dehydroepiandrosterone. 

Griffiths et al. [23] studied the ESI MS of sterols, and while they are not hormonal steroids, similar derivatization methods can be used. He converts 3/5-hydroxy-A5 sterols to - -4-ene sterols using cholesterol oxidase and follows this by preparation of Girard P hydrazones. This increases the sensitivity by 1000 in ESI. This technique would also be applicable to pregnenolone, dehydroepiandrosterone (DHEA) and similar A5 steroids, which can also be oxidized by cholesterol oxidase. 

The second method of preparation (shown in Scheme 2) depends on treating dehydroepiandrosterone (prepared from cholestrol or sitosterol) with acetylene to form the 17a-ethnyl-17p-hydroxy derivative, which is carbonated to the 17a-propionic acid. Reduction of the unsaturated acid in alkaline solution yields the saturated acid, which cyclizes to the lactone on acidification. Bromination to the 5,6-dibromo-compound, followed by oxidation of the hydroxyl group to the ketone, and then dehydro-bromination to the 7a-hydroxyl derivative, produces spironolactone when esterified with thiolacetic acid. 

An improved route has been described for the degradation of cholesterol to dehydroepiandrosterone,68,69 in which cholesterol is first acetylated and then bromi-nated to give the 5a,6/8-dibromide. This protected cholestane is then isomerized to the 5/3,6a-dibromide prior to chromium trioxide oxidation and zinc debromination. The yield of dehydroepiandrosterone (isolated from the reaction mixture as a 5a,6/3-dibromide) is 20%. 

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. 

The stereochemical argument can be closed with the observation that oxidation of dehydroepiandrosterone by the Oppenauer reaction (aluminum isopropoxide in the presence of a ketone) yields the oxidation product androst-4-ene-3,17-dione (14-1) (Scheme 1.14). The same diketone is formed from oxidation of testosterone (14-2). Going in the reverse direction, androst-4-ene-3,17-dione can be converted to testosterone by treatment with fermenting yeast. 

The prototypical 17-alkylandrogen, 17- methyltestosterone, is prepared from dehydroepiandrosterone (DHEA 1-5) in two steps. Reaction of DHEA with an excess of methylmagnesium bromide gives the corresponding 17-methyl derivative (13-1) (Scheme 5.13). Oppenauer oxidation then converts the hydroxyl at C3 to a carbonyl group the olefin shifts into conjugation in the process to give mestanolone (13-2). 

ABSTRACT This article describes physiological properties of two classes of natural products, namely cholesterol oxides and dehydroepiandrosterone (DHEA). The cholesterol oxides, also called oxysterols, are autoxidation products of cholesterol. Dehydroepiandrosterone and its sulfate DHEAS are formed mainly in the adrenals. The biological activities of these compounds are utilized to construct the two following hypotheses. 

Wittig-Horner reaction. This phosphonate has been used in a synthesis of progesterone (4) from dehydroepiandrosterone (2). One step in the conversion of (3) into (4) was an Oppenauer oxidation. The usual conditions (aluminum... 

---