Dehydroestrones

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Lupon P, Grau F, Bonet JJ. The photooxygenation of A9(u i-dehydroestrone and its 3-methyl ether. Helv Chim Acta 1984 67 332-333. 

Hydrogenation of d,l-9(ll)-dehydroestrone in tetrahydrofuran in the presence of Pd/CaC03 yields the estrone, melting point 251°-252°C (from acetone). 

The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(ll)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1. If). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-configuration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained... 

In the laboratory of T. Nakai, the asymmetric tandem Claisen-rearrangement-ene reaction sequence followed by a modified McMurry coupling was used to access (+)-9(11)-dehydroestrone methyl ether. The Claisen-ene product was subjected to ozonolysis and epimerization to the 8,14-anf/ configuration. The C-ring was constructed by treating the tricyclic diketo aldehyde with TiCl3-Zn(Ag) in DME to afford the desired final product in 56% yield. 

Mikami, K., Takahashi, K., Nakai, T. Asymmetric tandem Claisen-ene strategy for steroid total synthesis an efficient access to (+)-9(11)-dehydroestrone methyl ether. J. Am. Chem. Soc. 1990, 112, 4035-4037. 

Estrone (5) is rapidly oxidized at room temperature in either dioxane or methanol to A11 "-dehydroestrone (7, 67% yield).3 The quinone methide (6) is the probable intermediate, since (8) is also converted into (7). 

Preparation of estranes bearing substituents at position 6 relies on the availability of A° starting materials. In a typical example, 17-acetal-protected 6-dehydroestrone (27-1) is treated with an oxidizing agent such as peracetic... 

A slight modification of Corey synthesis (see Scheme 3.16) affords an estrane that bears a hydroxyl at C14. The 14-dehydroestrone intermediate from that synthesis is first reduced to give the corresponding 17[3-hydroxy analogue. This, in turn, is converted to its tert-butyldimethylsilyl ether (TBDMS) (32-1) by reaction with the silyl chloride (Scheme 3.32). Oxidation by means of w-chloroperbenzoic acid (mCPBA) affords the 14—15 epoxide 32-2 as a 3 1 mixture of a- and p-epimers. Treatment of the former with lithium aluminum hydride leads to the alcohol... 

Remote oxidation of estrone. Reaction of estrone (1) with this thallium(III) salt gives as the major products 2 and 3. The p-quinol 3 had been obtained earlier by oxidation of 1 with thallium(III) trifluoroacetate (4, 500-501). The ketone 2 is not formed via 3, which is stable to the oxidant, but it can be formed by oxidation of 9,11-dehydroestrone in the same way. ... 

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. 

Limits of 17/3-estradiol and A8,9-dehydroestrone Limit of estrone, equilin, and 17a-dihydroequilin (free steroids)... 

C16H2oBrN302, 1 2-Amino-11,1 3-diaza-9j3,14/3-11,1 2-dehydroestrone methyl ether hydrobromide, 35B, 331 Ci7H22BrN02, 8-Azaestrone hydrobromide, 34B, 289... 

Wolff—Kizhner methods led to the corresponding isomer of dehydro-doiS5molic acid (178) [284, 285], An attempt at the direct synthesis of (178) by the condensation of the diene (169) with oj-methyl-/ -acrylic acid was unsuccessful because of the undesirable structural directivity [286]. A repetition of the Arndt—Eistert reaction with (175) and Dieckmann cy-clization of the diester obtained (176) yielded the cis-C/D isomer of 8(9)-dehydroestrone (179) [287]. Dehydrogenation of the adduct (173) led to a naphthalene derivative (174), opening of the anhydride ring in which gave the semiester (177). The methyl ether of cis-equilenin (37) was obtained from the latter by two extensions of the side chain by the Arndt—Eistert reaction and by cyclization [283]. 

Azasteroids and their D-homo analogs have been obtained by Scheme 41 using as the starting material the quinolone (423), the tosylate or ben-zenesulfonate of which was converted via the vinyl carbinol (424), the diketone (425), and the tetracyclic ketone (427) into 6-aza-A -dehydroestrone (428) [535, 536]. However, the last stage of the synthesis, the hydrogenation of the 17-ketone (427), takes place unselectively in this case and in addition to the 14q -isomer of compound (428) C ield 26%), a predominating amount (yield 34%) of the unnatural 14/3 -isomer is formed. 

Like its six-membered homolog (553), the triketone (565) undergoes conversion on treatment with benzoic acid and triethylamine into the ACD diketone (566). In this case, however, the reaction takes place considerably more slowly, which is due to the increased strain introduced into the bicyclic system by the five-membered ring. The catalytic hydrogenation of (566) and the cyclization of the mixture of isomers formed (567) led to the methyl ether of -dehydroestrone (402) with an over-all yield of... 

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