Estrogen, total synthesis

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

The condensation of 6 methoxy-1-vinyl-l-tetralol with 2-ttifluoromethyl-l 3 cyclopentanedione in the presence of a small amount of triethylamine produces a secodione (equation 104) This dione is an intermediate in the total synthesis of 13-tnfluoromethyl estrogens, such as 18,18,18-tnfluoro 17(3 estradiol [121] Regwselecnve alkylation of a fluorinated (3-disulfone occurs at low tempera ture [122] (equation 105)... 

The dihydrobenzoxathiin 408, a potent selective estrogen receptor alpha modulator, is metabolized to the bridged dibenzo[, 4]thiopyran derivative 409. It seems logical to assume that 409 is formed by initial cleavage of the O-C bond followed by an intramolecular acylation to generate the thiopyran ring. A 19-step total synthesis from resorcinol confirmed the structure of 409 (Equation 115) <20050L411>. 

Vollhardt et al. The total synthesis of estrone, which is one of the three naturally occurring estrogens and a primary estrogenic component of several pharmaceutical preparations, was achieved in a few chemical operations [48]. Precursor 52 was prepared via consecutive cobalt(I)-mediated... 

The reagent has been used extensively by Velluz et at. for construction of ring A in the total synthesis of 19-norsteroids and estrogens, for example in the sequence... 

Because of their biological importance and widespread medical and industrial utilities, estrogens and related hormones are among the earliest targets in steroid total synthesis. Major efforts in the synthesis of these aromatic steroids were to set the correct chirality in the C,D rings since the A,B rings are mostly achiral. 

Chem. Common. 1967, 1253 Marshall, Deghenghi, Can, J Chem. 47, 3127 (1969). Component of Conjugated Estrogenic Hormones, q.v. Review of synthetic studies Taub, "Naturally Occurring Aromatic Steroids in The Total Synthesis of Natural Products vol, 2, J. ApSimon, Ed. (John Wiley Sons. New York, 1973) pp 664-670,... 

Total synthesis has become an important factor in the commercial production of steroids. Velluz and collaborators at Roussel have devised a practical method for the manufacture of 19-i steroids and estrogens Implicit in any total synthesis is the requirement for either a resolution or a stage of asymmetric reaction. Both methods have been used successfully to provide steroids of natural configuration. Of the two techniques the latter is to be preferred, since it is capable of converting all the substrate into useful product, whereas the former can only provide half of the product in natural configuration. 

Mikami and Nakai have investigated one-pot Claisen-ene sequence to achieve the asymmetric total synthesis of (-i-)-9(ll)-dehydroestron methyl ether [68]. Thus, the aUylic alcohol and cyclic enol ether in the presence of 2,6-dimethylphenol (10mol%) was heated in a sealed tube (Eq. 3.1.55). The tandem Claisen-ene product 91 was isolated in 76% yield after hydrolysis. The key feature of the present strategy is the successful development of the asymmetric tandem Claisen-ene sequence for the double carbocycUzation of D and C rings that allows for the relatively short constmction of the estrogen framework in a highly stereocontroUed fashion. 

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... 

Estrone is an estrogenic hormone. Tietze s group reported a very elegant method for the enantioseletive total synthesis of estrone (Scheme 7.2) [6]. The best part of the strategy is the generation of the steroid ring B through consecutive inter- and intramolecular Heck reactions. They discovered that the treatment of functionalized aromatic compound 5 and the enantiopure hydrindene derivative 6 with Pd(OAc)2 and PPhj in the presence of -Bu NOAc in a mixed DMF/MeCN/H O... 

In 2009, Snyder s group reported the first asymmetric total synthesis of ( )-napyradiomycin A1 93, a nonsteroidal estrogen antagonist isolated from Streptomyces bacteria... 

Alterations in the composition of the plasma lipids caused by estrogens are characterized by an increase in the high-density lipoproteins (HDL), a slight reduction in the low-density lipoproteins (LDL), and a reduction in total plasma cholesterol levels. Plasma triglyceride levels are increased. Estrogens decrease hepatic oxidation of adipose tissue lipid to ketones and increase synthesis of triglycerides. 

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