Estrogenic steroids synthesis

In the following decades, chemists tried to utilize more and more the knowledge on reactions which had already been gained. A number of landmark syntheses represent the change to modern chemistry, such as the synthesis of the estrogenic steroid equilenin (W. Bachmann, 1939), of pyridoxine (K. Folkers, 1939), and of quinine (R.B. Woodward, W. von E. Doering, 1944) [23]. 

The distribution, between the placenta and fetus, of the activity of some of the major enzymes involved in steroid synthesis is shown in Table 2. After birth the lack of 3/3-HSD, the aromatizing enzymes, and sulfotransferases is not compensated for by the placenta, with the result that (a) only relatively small quantities of 3-oxo-A steroids are formed, but despite this, cortisol production is adequate (see Section 7.3) (b) the newborn infant cannot convert its large supply of estrogen precursors to estrogen and (c) it cannot desulfurylate its steroids, which have been sulfated by the considerable and widely distributed activity of sulfotransferases (B24, W3). 

FIGURE 12.1 Biosynthesis of estrogens. Abbreviations DHEA, dehydroepiandrosterone El, estrone E2, estradiol T, testosterone DHT, dihydrotestosterone. Letrozole is an aroma-tase inhibitor, Finasteride is a 5a-reductase inhibitor. Androstane-3p,17P-diol (SPO) is an estrogenic steroid and its synthesis is blocked by 5a-reductase inhibitor, but not affected by aromatase inhibitor."... 

Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. One notable exception, however, was the first industrial-scale synthesis of optically active steroids performed by workers at Roussel-UCLAF. The linear synthesis began with a suitable B—C-ring synfhon, 6-methoxy-l-tetralone (186). In a series of steps, tetralone (186) was converted to 2-methyl-2-cyanotetralone (270). Condensation of (270) with dimethyl succinate followed by carbonyl reduction, saponification, and resolution produced the optically active tricyclic acid (271). A series of reductions, a decarboxylation, and a hydrolysis produced (272). Appendage of the A-ring functionality by alkylation produced intermediate (273). Compound (273) was used as a common intermediate for the synthesis of 19-norsteroids, estrogens, and corticosteroids (230). 

See also Estrogens, Steroid Hormone Synthesis, Steroid Metabolism, Steroid Hormones... 

The clinical uses of anastrozole (decreases estrogen synthesis), danazol (deaeases ovarian steroid synthesis), clomiphene (decreases feedback inhibition), and the selective estrogen-receptor modulators tamoxifen and raloxifene are considered. 

In the membranes of the endoplasmic reticulum, the enzyme P450cn catalyzes the hydroxylation of C17 of progesterone or pregnenolone and can also catalyze the cleavage of the 2-carbon side chain of these compounds at C17 (a C17-C20 lyase activity). These two separate functions of the same enzyme allow further steroid synthesis to proceed along two separate pathways the 17-hydroxylated steroids that retain their side chains are precursors of cortisol (C21), whereas those from which the side chain was cleaved (C19 steroids) are precursors of androgens (male sex hormones) and estrogens (female sex hormones). 

Several total syntheses of estrogenic hormones and, in the first place, of derivatives of equilenin have been carried out by this route. The principles of the approach to total steroid synthesis considered in this chapter generally come up against serious obstacles even in their application to estrone derivatives. Moreover, their application to the synthesis of nonaromatic steroids has generally been unsuccessful. 

The structurally simplest steroids, the aromatic A ring estrogens, have ironically proven most difficultly accessible because this aromatic ring is not found in any of the plant sterols available in commercial quantities. The main task of partial synthesis from naturally occurring material thus becomes... 

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