Birch reduction of estradiol 3-methyl ether

A carbonyl group cannot be protected as its ethylene ketal during the Birch reduction of an aromatic phenolic ether if one desires to regenerate the ketone and to retain the 1,4-dihydroaromatic system, since an enol ether is hydrolyzed by acid more rapidly than is an ethylene ketal. 1,4-Dihydro-estrone 3-methyl ether is usually prepared by the Birch reduction of estradiol 3-methyl ether followed by Oppenauer oxidation to reform the C-17 carbonyl function. However, the C-17 carbonyl group may be protected as its diethyl ketal and, following a Birch reduction of the A-ring, this ketal function may be hydrolyzed in preference to the 3-enol ether, provided carefully controlled conditions are employed. Conditions for such a selective hydrolysis are illustrated in Procedure 4. 

TABLE 1-5 Effect of Iron on the Birch Reduction of Estradiol 3-Methyl Ether by Lithium, Sodium and Potassium" ... 

A remarkable feature of the Birch reduction of estradiol 3-methyl ether derivatives, as well as of other metal-ammonia reductions, is the extreme rapidity of reaction. Sodium and -butyl alcohol, a metal-alcohol combination having a comparatively slow rate of reduction, effects the reduction of estradiol 3-methyl ether to the extent of 96% in 5 minutes at —33° lithium also effects complete reduction under the same conditions as is to be expected. Shorter reaction times were not studied. At —70°, reduction with sodium occurs to the extent of 56 % in 5 minutes, although reduction with lithium is virtually complete (96%) in the same time. (The slow rates of reduction of compounds of the 5-methoxytetralin type is exemplified by 5-methoxy-tetralin itself with sodium and f-butyl alcohol reduction occurs to the extent of only 50% in 6 hours vs. 99+% with lithium.) The iron catalyzed reaction of sodium with alcohols must be very fast since it competes so well with the rapid Birch reduction. One cannot compensate for the presence of iron in a Birch reduction mixture containing sodium by adding additional metal to extend the reaction time. The iron catalyzed sodium-alcohol reaction is sufficiently rapid that the aromatic steroid still remains largely unreduced. 

Birch reduction of estradiol 3-methyl ether at 0.12M concentration, 50... 

The product from Birch reduction of estradiol 3-methyl ether, nandrolone, 1-5, comprises one of the simplest androgens in the gonane series. This compound suffers extremely fast metabolic inactivation by attack at C17 most androgens consequently incorporate an additional substituent at that position. 

The sequence for preparing the first oral contraceptives thus starts by Birch reduction of estradiol 3-methyl ether (14-1) to afford the 1,4-dihydro derivative 14-2 (Scheme 4.14). The enol ether in this product is sensitive to acid, mandating that the succeeding reactions be carried out under neutral or slightly basic conditions. The hydroxyl at C17 in... 

Reduction of derivatives of estradiol 3-methyl ether (I) and hydrolysis of the initially formed enol ether II provides an efficient route to 19-norsteroids (111) of considerable importance in hormone therapy. A. J. Birch, who introduced the method (1949), used sodium in liquid ammonia with ethanol as proton donor. A. L. Wilds and N.A. Nelson (1953) found that yields are improved by use of lithium in place of sodium and that lithium is effective in some cases where sodium is not. The Wilds-Nelson procedure, which became the standard one, employs ether as co-solvent and involves adding the ethanol lust terminal decomposition is done with water after evaporation of ammonia, Since this reaction is the key step in processes developed by O. D. Searleand Co. for the production of two I V-norsteroids... 

The Birch reduction of the methyl ether of rfZ-estradiol (407) has permitted the preparation of 19-nortestosterone (406), also synthesized independently from the -dehydro derivative (404). In the second case, however, the reduction of the A )-bond takes place nonselectively and with the (406) is formed its 9j8, lOa-isomer, amounting to about l/3 of the mixture of products. The third variant of the synthesis, from the A ( )-ketone (403), proved to be the most suitable, enabling (406) to be obtained in a single stage with an over-all yield of 55% [95, 489, 496]. Passage to derivatives of 19-norandrostane has also been effected by the Birch reduction of the ketals (393) and (401) [95,496] of the 17o -alkyl derivatives obtained from the ketone (403) and its 13-alkyl homologs [442, 488, 503, 504, 518-520] and also of the methyl ether of 8-isoestrone (368) and its 17 -dihydro and 13-alkyl derivatives. J... 

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