Estradiol synthesis

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of halides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsiiyl cyanide in EtiN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

The estrogens are a family of hormones synthesized in a variety of tissues. 17P-Estradiol is the primary estrogen of ovarian origin. In some species, estrone, synthesized in numerous tissues, is more abundant. In pregnancy, relatively more estriol is produced, and this comes from the placenta. The general pathway and the subcellular localization of the enzymes involved in the early steps of estradiol synthesis are the same as those involved in androgen biosynthesis. Features unique to the ovary are illustrated in Figure 42-7. 

NT318 Gocze, P. M., 1. Szabo, and D. A. Freeman. Influence of nicotine, cotinine, anabasine and cigarette smoke extract on human granulose cell progesterone NT331 and estradiol synthesis. Gynecol Endocrinol 1999 13(4) 266-272. 

Few studies have investigated the reproductive toxicity of DEHP in female animals. When female mice were exposed to a dietary dose of 420 mg/kg/day DEHP for 105 days and mated with unexposed males, combined weights of the ovaries, oviducts, and uterus were reduced, and no litters were produced. When female mice exposed to 14 or 140 mg DEHP/kg/day were mated with males given these same doses, there was a dose-related decline in the number of litters, live pups per litter, and live pup weight. Short-term gavage exposure to a very high level of DEHP (2,000 mg/kg/day), particularly with respect to possible human exposure, had clear effects on estradiol synthesis, manifested as decreased serum estradiol levels and anovulatory cycles and polycystic ovaries, in female rats. These data indicate that oral exposure to DEHP can affect reproductive processes in female rodents. 

Figure 33.9. The two-cell-two-gonadotropin model of estradiol synthesis in ovarian follicles. (Adapted from and reproduced with permission from Carr, B. R., MacDonald, P. C., and Simpson, E. R. The role of lipoproteins in the regulation of progesterone secretion by the human corpus luteum. Fertil. Steril. 38, 303-311, 1982.)...

In cultured porcine granulosa cells, NO has been implicated as a negative regulator of steroidogenesis (Masuda et al., 1997). Treatment of purified granulosa cells with an NO donor resulted in decreased aromatase activity (Masuda et al., 1997). Furthermore, inhibition of NOS resulted in a dose-dependent increase in estradiol synthesis from both basal and gonadotropin-stimulated cells (Masuda et al., 1997). 

Olson, L.M., Jones-Burton, C.M., and Jablonka-Shariff, A. (1996b). Nitric oxide decreases estradiol synthesis of rat luteinized ovarian cells Possible role for nitric oxide in functional luteal regression. Endocrinology fi7 3531-3539. 

In (he ttvary. FSH (and LH) stimulates follicular development (middle left. A-B) and estradiol synthesis by the granulosa cells of ilie follicle. In the early follicular phase, the low esiradio level in the blood (middle leR) exerts a negative feedback effeei on FSH, ensuring that... 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

Very Htfle data are available regarding effects of anaboHc steroid implants on the Hpid metaboHsm in growing mminants. Lipogenic enzyme activity and fatty acid synthesis in vitro were elevated in subcutaneous adipose tissue from bulls implanted with estradiol (44), which may account for the increase in fat content of carcasses reported in some studies. TBA implants have no effect on Hpogenesis in intact heifers, and only tend to reduce Hpogenic enzyme activities in ovariectomized heifers (45). 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

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)... 

Le Bras, J. Rager, M. N. Besace, Y. Vaissermann, J. Amouri, H. Activation and regioselective ortho-functionalization of the A-ring of P-estradiol promoted by Cplr an efficient organometallic procedure for the synthesis of 2-methoxyestradiol. Organometallics 1997, 16, 1765-1771. 

To date, only a few examples are known where a domino reaction starts with an electrocydic reaction, although the value of this approach is clearly demonstrated by the beautiful synthesis of estradiol methyl ether 4-319 through a domino elec-trocyclic/cycloaddition process. There is also an impressive example of a double thermal electrocyclization being used however, the starting material for this domino reaction was prepared in situ by a transition metal-catalyzed transformation, and is therefore discussed in Chapter 6. 

For the synthesis of estradiol methyl ether 4-319, the cydobutene derivative 4-317 was heated to give the orthoquinonedimethane 4-318 which cydized in an intramolecular Diels-Alder reaction [109]. The thermally permitted, conrotatory elec-trocyclic ring-opening of benzocyclobutenes [110] with subsequent intramolecular cycloaddition also allowed the formation of numerous complex frameworks (Scheme 4.70). 

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