Estradiol derivatives, synthesis

M. E. Brewster, K. S. Estes, N. Bodor, Improved Debvery through Biological Membranes. 32. Synthesis and Biological Activity of Brain-Targeted Debvery Systems for Various Estradiol Derivatives , J. Med. Chem. 1988, 31, 244-249. 

Other authors have described the lipase-catalyzed chemoselective acylation of alcohols in the presence of phenolic moities [14], the protease-catalyzed acylation of the 17-amino moiety of an estradiol derivative [15], the chemoselectivity in the aminolysis reaction of methyl acrylate (amide formation vs the favored Michael addition) catalyzed by Candida antarctica lipase (Novozym 435) [16], and the lipase preference for the O-esterification in the presence of thiol moieties, as, for instance, in 2-mercaptoethanol and dithiotreitol [17]. This last finding was recently exploited for the synthesis of thiol end-functionalized polyesters by enzymatic polymerization of e-caprolactone initiated by 2-mercaptoethanol (Figure 6.2)... 

Vessieres A, Jaouen G, Gruselle M, Rossignol JL, Savignac M, Top S, Greenfield S (1988) Synthesis and receptor binding of polynuclear organometallic estradiol derivatives. J Steroid Biochem 30 301-306... 

Based on the use of 4-methoxybenzocyclobutene-1-carboxylic acid, racemic homoestrone has been synthesised (ref. 124). A strategy based on boron annulation led not directly to estrone but to a synthesis of norpregnenolone which was then degraded by standard procedures to afford estradiol derivatives (ref. 125). 

Condensation of 88 with 77 and reductive removal of the cyano function gave key intermediate 90. Thermolysis as in the previous synthesis led in 84% yield via an exo transition state to the chromatographically pure chiral estradiol derivative 91, in turn deprotected to (-I-)-estradiol 40. 

Tietze et al. [83] were interested in the synthesis of medium-ring-sized estradiol derivatives such as 214 (Scheme 5.37). Mizoroki-Heck reaction of 213a in the presence of the Herrmann-Beller catalyst proceeded well and provided 214a without 8-c do-trig side-product in high yield (80%) and a 4 1 ratio of exocyclic to endocyclic (not shown)... 

FIGURE 11.53 Hydroxysteroid derivatives with two levels of molecular diversity. (From Tremblay, M.R. and Poirier, D., Solid-phase synthesis of phenolic steroids from optimization studies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives, J. Comb. Chem., 2,48, 2000 Maltais, R., Tremblay, M.R., and Poirier, D., Solid-phase synthesis of hydroxysteroid derivatives using the diethylsi-lyloxy linker, J. Comb. Chem., 2, 604, 2000.)... 

FIGURE 11.56 Library of 4-para-substituted phenylvinyl estradiol derivatives. (From Hanson, R.N. et al.. Synthesis and evaluation of 17-201i-21-(4-substituted phenyl)-19-norpregna-l,3,5(10), 20-tetraene-3,17P-diols as probes for the estrogen receptor a hormone binding domain, J. Med. Chem., 46, 2865, 2003.)... 

Tremblay, M.R. and Poirier, D., Solid-phase synthesis of phenolic steroids from optimization stndies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives, J. Comb. Chem., 2, 48, 2000. 

Tremblay MR, Poirier D. Sohd-phase synthesis of phenolic steroids towards combinatorial hbraries of estradiol derivatives. Tetrahedron Lett. 1999 40 1277 1280. 

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-... 

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]. 

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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