17/3-Estradiol steroidal analogs

Tietze and his co-workers prepared estradiol and a number of other steroid derivatives using a compact sequential Heck reaction approach. Compound 51 was obtained from the known Hajos-Wiechert ketone derivative 50 in 3 steps. Heck reaction with palladium(II) acetate in the presence of triphenylphosphine gave intermediate 52, the precursor of the second Heck reaction. Additional steps converted steroid analog 53 into estradiol (54). 

Reaction of estrone with a metal acetylide affords 17a-ethynyl-173-hydroxy-estradiol (etbynylestradiol, 30a EE). This compound is equipotent with estradiol by subcutaneous administration, but it is 15 to 20 times as active when administered orally. Ethynylation of the methyl ether of estradiol analogously affords mestranol (30b), It should be noted that the same factors apply in these reactions as in previously discussed reductions at 17 almost the sole products of these reactions are those which result from attack of reagent from the least hindered a side of the steroid. Ethynylestradiol and mestranol are of special commercial significance since the majority of the oral contraceptives now on sale incorporate one or the other of the compounds as the estrogenic component. 

An alternative reaction path (category 2) may compete effectively with rearrangement in dienones which possess other than alkyl or phenyl substituents in the 7-position. Thus, the steroid derivative 58 gave estradiol monoacetate (60) on photolysis in dioxane (Chart 9). In the cases of the hydroxy analog 59 (- 60 + 139) and the methoxy dienone 61 (- 62 63),the two paths—rearrangement to isomers and... 

Androgens have a 19-carbon nucleus and serve as precursors to more potent analogs produced in the periphery. The adrenal gland can synthesize estradiol and estrone from testosterone and androstene-dione, respectively however, the quantities are extremely small. The rates of production for the various steroids produced by the adrenal gland are listed in Table 74—1. 

Steroidal SERM-Type Antagonists Several steroidal ER antagonists have been described in the literature. It was established that attachment of a side-chain to the 11- or 7-position of 17(5E2 or 17P-ethinyl-estradiol converts the molecules from agonists into antagonists. Aventis Pharma (formerly Hoechst Marion Roussel) disclosed 17PE2 and 17P-ethinyl-estradiol analogs having a SERM-type BSC attached to the... 

Rearrangements of cyclopropanes. Cyclopropanes are interesting not only by themselves, but also because they are easily converted into important synthons in organic chemistry. Recently, rearrangements of cyclopropanes have appeared in the synthesis of, namely, steroids (pregn-4-en-one) [58], 19-norsteroids (estrone, 19-norandrost-4-en-3-17-dione, estradiol-17,8)and 19-nortestosterone [59], insect juvenile hormone analogs [60]. 

Many analogs of the endogenous steroids 17p-estradiol, 17P-testosterone, and progesterone (Fig. 1) have been developed by the pharmaceutical industry for therapeutic purposes. Functional groups have been modified or added, by small or larger chemical modifications, to alter the strength and mode of action, to enable oral administration, and to influence other pharmacokinetic properties. 

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