Synthesis of estrogens

Fig. 23. Asyimnetiic total synthesis of estrogens, where TBS = tert — butyldimethylsilane.

Xenobiotic induced disruption of female fertility follows essentially the same pattern as that of the male and can be caused by changes in pituitary-hypothalamic function, primary disruption of ovarian structure or hormone secretion, or changes in the rate of hormone deactivation. In addition, there may be changes in the synthesis of estrogen induced production of the yolk protein by the liver (vitellogenesis), which in turn can lead to failure to lay down sufficient yolk in the developing oocytes. Vitellogenesis provides a valuable biomarker for endocrine dysfunction in both sexes,but is more properly considered as part of the liver function. 

Estrogens are produced mainly by the ovary and the placenta and the synthesis of estrogens takes place from cholesterol (as discussed in section on glucocorticoids ). Estrogens are classified into two main groups (see table 8.3.2). 

Figure 1. Major steroids in the synthesis of estrogen from cholesterol.

Aminoglutethimide [ah me no glue TETH i mide] is useful in second line therapy for the treatment of metastatic breast cancer. It inhibits the adrenal synthesis of pregnenolone from cholesterol, and the extra-adrenal aromatase reaction responsible for the synthesis of estrogen from androstenedione. Aminoglutethimide is administered orally, and is metabolized by the hepatic cytochrome P-450 system to inactive products. Because of its ability to induce this system, its own metabolism is accelerated, and interactions that increase the metabolism of dexamethasone (see p. 275), theophylline (see p. 220) and digoxin (see p. 158) can occur. Aminoglutethimide causes transient CNS depression and a maculopapular rash. 

Aromatase inhibitors serve to eliminate ex-traovarian synthesis of estrogens in breast cancer patients. This can be achieved effectively only in postmenopause because, as an FSH-dependent enzyme, ovarian aromatase is subject to feedback regulation of female Luellmann, Color Atlas of Pharmacology 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Placental synthesis of estrogens. The placenta lacks the key enzyme necessary for formation of estrogens from cholesterol (CYP 17) and relies on androgenic precursors from the maternal and fetal compartments. The major androgen used comes from the fetal zone of the fetal adrenal this is DHEAS, which is also taken up and metabolized by fetal liver into Iba-hydroxy-DHEAS. The placenta converts DHEAS into estrone (E ) and estradiol (E2) and proces.ses 16a-hydroxy-DHEAS into estriol (Ej). Estrogens enter the maternal circulation and appear in maternal urine as conjugated estrogens. 

Certain breast cancers require estrogen to grow. Aromatase inhibitors, because they block the synthesis of estrogen, are a new class of drugs used in the treatment of breast cancer in postmenopausal women. 

Fink B. A, Mortensen D. S, Stauffer S. R., Aron Z. D, Katzenellenbogen J. A. Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens, Chem. Biol. 1999. p. 205 -219. DOI 10.1016/ S1074-5521(99)80037-4... 

An example of a chemical that Impacts the reproductive ability of both sexes Is ethanol, found in alcoholic beverages. In males all stages of sperm development within the testis are affected in females ethanol appears to act by interfering with the synthesis of estrogen by the ovaries. In addition, we know that ethanol consumption during pregnancy can lead to deformities and fetal alcohol syndrome. 

Robinson s group have developed several methods of obtaining derivatives of 1,3-cyclohexanedione, the intramolecular cyclization of which makes it possible to obtain intermediates for the total synthesis of estrogens (Scheme 48). The condensation of the acid chloride (74) (obtained in six stages from m-methoxybenzaldehyde) with a-acetylglutaric ester... 

Another variant of the synthesis of estrogens described in Schemes 52-54 has also been developed. The successive reaction of compound (548) with ethyl magnesium bromide, formaldehyde, and phosphorus tribromide led to the bromide (I) with a yield of Conversion of the bromide (I) into the AD fragment (II) was successfully achieved by reaction with the sodium salt of 2-methyl-1,3-cyclopentanedione in dimethyl sulfoxide. Cyclization of the intermediate (II) with polyphosphoric acid gave the A -bisdehydro derivative (395) [T. Hiraoka and I. Iwai, Chem. Pharm. Bull. (Tokyo), 14 262 (1966)]. 

Syntheses via BCD Intermediates with a Five-Mem-bered Ring D. These syntheses generally start from 6-methoxy-l-tetralone or its 5-methyl derivative, which are used as the BC fragments. All the methods used in Chapter II for the synthesis of estrogenic hormones from 14-oxa compounds are employed for the construction of ring D. It must be mentioned that some of the intermediates illustrated in Schemes 70 and 71 have also been obtained by syntheses of the BD - C type (cf. Section 3 of this chapter). 

This coupling reaction of alkenylgermanes can be applied to the synthesis of estrogen receptor modulator tamoxifen (112), which is used in the clinical treatment of estrogen-dependent breast cancer (Fig. 40). The benzoyl triethylgermane (108) is olefinated with ynolate to give the aUcenylgermane 109, which is coupled... 

SCHEME 4.27. Practical asymmetric synthesis of estrogen receptor-P selective agonist. 

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