18-Hydroxyestrone-3-methyl ether

Magnus and co-workers7 have used a related desilylation for a novel synthesis of I la-hydroxyestrone methyl ether (8) from the epoxide (7) via an o-xylylene intermediate,... 

Contemporaneous with the work of Ito was a synthesis of 11-a-hydroxyestrone methyl ether (148) by Magnus and coworkers (Scheme 54) ° in which the requisite o-quinodimethane interm iate was generated by the fragmentation of the o-[(trimethylsilyl)methyl]aryl oxirane derivative (147) using CsF. 

An alternate ethynylating reagent is the lithium acetylide-ethylene-diamine complex which is available commercially. This reagent in dimethyl sulfoxide solution has been used to ethynylate 11 j -hydroxyestrone and its 3-methyl ether. 

Mild acid then cleaves off the silyl protecting group. The alcohol at position 17 is then oxidized with Jones reagent (chromium trioxide in acetone) to afford 14a-hydroxyestrone 3-methyl ether (32-5). 

The oxidation of phenols via HAT from the hydroxyl group (or sequential electron transfer and deprotonation) is supported by data on the oxidation of estradiol and estrone. In accord with a key role for the phenolic hydroxyl group, the predominant ortAo-hydroxylation of estradiol does not occur when the phenolic hydroxyl is replaced by a methyl ether . Early experiments established that 2-hydroxylation of estradiol occurs without a detectable NIH shift . More recent work has shown that, whereas estrone is converted to both 2- and 4-hydroxyestrone by CYP3A4, conjugation of an additional aromatic ring, as in equilenin and 2-naphthol, leads exclusively to 4-hydroxylation of estrone and 1-hydrox-ylation of 2-naphthol. In both these reactions, the site that is exclusively hydroxylated is that expected to carry the greatest share of the unpaired electron density if the initial step is... 

Kametani has also described analogous routes to 14a-hydroxyestrone-3-methyl ether, (- )-3p-hydroxy- 17-methoxy-D-homo-18-nor-5a-androst-13,15,17-triene (a key intermediate in Nagata s synthesis of pregnanes), as well as other ring D aromatic D-homosteroids, and their conversion into various classes of pregnanes. Generation of dienes from tetrahydrobenzocyclobutene [bicy-clo(4,2,0)oct-l(6)-ene] systems has been accomplished and could lead to direct routes to saturated steroids. 

Tsuji and his group have developed a palladium catalyzed cyclization reaction that has led to a simple synthesis of 2-carbomethoxy-3-vinylcyclopentanone 142, which they have utilized in syntheses of cyclopentanoid natural products. In the steroid field, 142 served as a ring D component in an orthoquinodimethane-based route to ( )-18-hydroxyestrone. The (-I-)-diastereomer is a component of pregnancy urine. ( )-Estradiol-3-methyl ether was also obtained (Scheme 19). ... 

Magnus et al. have devised a route to ( )-lla-hydroxyestrone 3-methyl ether which, like the Saegusa synthesis (Scheme 20), makes use of fluoride mediated elimination of the trimethylsilyl group, but which is coupled with alternative methodology for in situ orthoquinodimethane generation (Scheme 21). ... 

Synonyoa 2,3-Dihydroxy-l,3,5[10]-estratrien-17-one-2-methyl ether 2-hydroxyestrone-2-methyl ether 3-hydroxy-2-methoxy-l,3,5[10] estratien-17-one Trade namea ... 

Aq. NaNOg added dropwise with swirling at 0° to a soln. of 4-aminoestrone 3-methyl ether in 10%-H2SO4, allowed to stand 20 min. at 0 with frequent agitation, then aq. 40%-urea added, kept 5 min. at 0°, added to ice-cold water, and UV-irradiated at 0° for 6 hrs. 4-hydroxyestrone 3-methyl ether. Y 79-98%. F. e. with lower yield s. S. Kraychy, Am. Soc. 81, 1702 (1959). 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

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