Dehydroepiandrosterone from cholesterol

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

Miller WL. Disorders of androgen synthesis—from cholesterol to dehydroepiandrosterone. Med Princ Pract. 2005 14(suppl l) 58-68. 

In most mammals, estrogens (female sex steroid hormones) are synthesized from cholesterol using the parent ring structure, cyclopentanoperhydrophenan-threne of the estrane series. The steroidogenic pathway includes the production of the androgenic precursors dehydroepiandrosterone and androstenedione, the latter of which is converted to testosterone, then to estradiol-17/i. This requires aromatization of these andogenic precursors by an aromatase enzyme complex. The major source of estrogen in postmenopausal women is the conversion of androstenedione to estrone by aromatase activity... 

Fig. 1 Human steroidogenic pathway from cholesterol to adrenal or gonadal steroid products. CYP cytochrome P450 enzyme, ftSfthydroxysteroid dehydrogenase, DHEA dehydroepiandrosterone, Oft hydroxy, arom aromatase...

DHEA (dehydroepiandrosterone) is another nonprescription antidepressant that has gone through cycles of popularity (Figure 6.2). DHEA, a steroid, is made from cholesterol in the adrenal gland and is part of the biochemical pathway in which hormones such as estrogen and testosterone are end-products. While its properties as a peripheral hormone are well characterized, less is known about DHEA s function in the brain. Media interest in DHEA arose when it was shown to prevent or slow memory loss in older populations. Further research showed that DHEA could influence neuronal function in the hippocampus, a region important for memory formation. However, several clinical studies showed mixed results when DHEA was used in... 

It has been suggested that dehydroepiandrosterone can be formed directly from cholesterol, through either a 17a,20a-dihydroxycholesterol or 17a,20a,22-trihy-droxycholesterol. 

The 1,4-addition of alkyl cyanocupratcs to epoxides to form cyclic a,ft-unsalurated ketones provides a stereoselective method for conversion of dehydro-. cpiandrosteronc into cholesterol (4) and other related steroids. Thus the keto epoxide 2 (obtained from dehydroepiandrosterone in 55% overall yield in three steps) reacts with lithium isohcxylcyanocupratc to give the adduct 3, which can be converted to cholesterol (4) in several known steps.27... 

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%. 

Figure 8-2. Synthesis of the steroid hormones. The rings of the precursor cholesterol are lettered. Dihydrotestosterone is produced from testosterone by reduction of the C - C double bond in ring A. DHEA = dehydroepiandrosterone.

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. 

F. 34.23. Synthesis of the steroid hormones. The rings of the precursor, cholesterol, are lettered. Dihydrotestosterone is produced from testosterone by reduction of the carbon-carbon double bond in ring A. Structural changes between the precursor and final hormone are noted in blue. DHEA = dehydroepiandrosterone. The dashed lines indicate alternative pathways to the major pathways indicated. The starred enzymes are those that may be defective in the condition congenital adrenal hyperplasia. 

The discovery of oestrone (VII) in 1929 by Doisy and independently by Butenandt was followed in 1934 by the isolation of progesterone (II) from corpus luteum tissue and of dehydroepiandrosterone (IV) from urine (see review by Petrow [16]). Although their chemical structures were not fully elucidated, a relationship between them and cholesterol was assumed. 

In another pathway, 17a,20a-dihydroxycholesterol. or 17a,20a-trihydroxycholesterol is an intermediate between cholesterol and dehydroepiandrosterone. Androgens are also assumed to be synthesized in liver and nongonadal tissue from 21-hydroxylated derivatives such as 3j8,17a,21 -trihydroxy-5a-pregnane-11,20-dione and 11-deoxycorticosol, which by splitting of the side chain yield dehydroepiandrosterone or androst-4-ene- 3,17-dione. 

Srinivas and Srinivasulu (1993) found that heulandate layers developed with carbon disulfide-pyridine (1 1) were effective for the separation of steroid hormones,—dehydroepiandrosterone could easily be separated from mixtures of cholesterol and estradiol benzoate or testosterone phenylpropionate, and testosterone could be separated from mixtures of cholesterol and testosterone phenylpropionate or estradiol benzoate. Likewise, estradiol could easily be separated from mixtures of cholesterol and estradiol benzoate. Daeseleire et al. (1994) applied HPTLC and GC/MS for the detection of anabolic steroids used as growth promoters in illicit cattle fattening within the European market. Agrawal et al. (1995) developed a sensitive, reliable, and rapid silica gel TLC method for the separation, identification, and quantification of stereospecific androgen metabolites. 

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