Equilenin methyl ether

The A-ring of the 17-ol (25) derived from equilenin 3-methyl ether is reduced rapidly under Birch reduction conditions, since the 1,4-positions are unsubstituted. The B-ring is reduced at a much slower rate, as is characteristic of aromatic compounds in which 1,4-reduction can occur only if a proton enters an alkylated position. Treatment of (25) with sodium and t-butyl alcohol in ammonia reduces only the A-ring to afford the corresponding 1,4-dihydro compound in over 85% yield.On the other hand,... 

Although one successful synthesis of equilin from equilenin methyl ether has been reported, Birch reductions of such substrates are non-selective, since reduction of both aromatic rings occurs. Use of the free phenol in such reductions, however, has neatly overcome these difficulties. Formation of the naphthoxide ion prior to Birch reduction with lithium-ammonia at — 70 °C has resulted in high yields of equilin. Surprisingly, further reduction of equilin 17-dimethylketal... 

Posner and co-workers have developed an efficient (52% overall yield) conversion of 2-methyl-2-cyclopentenone into ( )-ll-oxoequilenin methyl ether, 4 (Scheme 1). TTie latter had been hydrogenolyzed earlier to equilenin methyl ether by Birch (see Volume 2, p. 660). 

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... 

A comparison with the results obtained in the cyclization of phenan-threne analogs of acid (67) [202] and products not containing an angular methyl group [195, 203] shows that in this case cyclization may take place either at C13 with the participation of the double bond or at C7 with the participation of the aromatic ring. The best cyclization procedure proved to be that carried out in acetic anhydride under the action of traces of zinc chloride, which forms the tetracyclic products (33) and (68) with a slight predominance of the first of them [164, 199]. The conversion of the unsaturated ketone (33) into the methyl ether of equilenin (36) has been discussed in Scheme 4. 

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]. 

Recently, the methyl ether of c /-equilenin has been obtained from the acid (270) [A. J. Birch, G. S. R. Subba Rao, Tetrahedron Letters, 1967 2763]. tAn analog of (274) with a six-membered D ring and the trans-C/D linkage, which is more stable in this case (the methyl ether of d/-18-nor-D-homoequilenin) has also been synthesized from the methoxyketone (266) by a method similar to that described in Scheme 26 [381, 382]. 

A. Carbocyclic - A few new methods are available to prepare the steroidal skeleton. For tne most part, these involve variations of the previously reported methods for the total synthesis of steroids. Racemic equilenin is prepared stereo-specifically starting with 2-bromo-6-methoxynaphthalene and the i "butyl enol ether of 2-methyl-l,3-cyclopentanedione. Estrone was prepared from the cheap natural product eugenol the key intermediate m-methoxyallylbenzene. Progress toward the total synthesis of terpenes, specifically the pentacyclic triterpene alnusenone, is reported. The synthesis of B-nor, B-nor-D-homo, or normal steroids by the use ot an electrophilic reagent on a bicyclic enamine is recorded. In addition, a bicyclic intermediate can be converted into a D-homo-8g-methyl-B-norestrane. ... 

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