Enolates estradiols

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

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. 

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

The general reaction procedure and apparatus used are exactly as described in Procedure 2. Ammonia (465 ml) is distilled into a 2-liter reaction flask and to this is added 165mlofisopropylalcoholandasolutionof30g(0.195 mole) of 17/ -estradiol 3-methyl ether (mp 118.5-120°) in 180 ml of tetrahydrofuran. The steroid is only partially soluble in the mixture. A 5 g portion of sodium (26 g, 1.13 g-atoms total) is added to the stirred mixture and the solid dissolves in the light blue solution within several min. As additional metal is added, the mixture becomes dark blue and a solid (matted needles) separates. Stirring is inefficient for a few minutes until the mass of crystals breaks down. All of the sodium is consumed after 1 hr and 120 ml of methanol is then added to the mixture with care. The product is isolated as in Procedure 4h 2. After being air-dried, the solid weighs 32.5 g (ca. 100% for a monohydrate). A sample of the material is dried for analysis and analyzed as described in Procedure 2 enol ether, 91% unreduced aromatics, 0.3%. The crude product may be crystallized from acetone-water or preferably from hexane. 

Some compounds fluoroalkylated in position 7a of estradiol have also been prepared by electrophilic fluoroalkylation of corresponding enol derivatives (cf. Figure 2.37 in Chapter 2, and Figure 8.74 in Chapter... 

The retention of tritium at C(2) in the conversion of testosterone to estradiol is interpreted as the result of triitium IE associated with enolization of 4-dien-3-one intermediate. The enolization follows after the deformylation and 1/i-hydrogen abstraction steps and is... 

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... 

When 17/3-estradiol C(17) fatty acid esters such as 134 are deprotonated under NCI(NH3) conditions, two tautomeric [M — H] ions are generated, one being the 3-phenolate form [134 — and the other the ester enolate [134 —... 

Estradiol and estrone are metabolized to an array of oxidized products, one of which consists of the 16a-hydroxy derivative 30-4. One approach to preparing that compound starts by reaction of estrone with isopropyhdene acetate, to afford the acetate of the enolic form of the ketone and also the ester of the phenol at position 3 (30-1) (Scheme 3.30). Treatment of that product with perbenzoic acid leads to the a-oxirane 30-2, formed from approach of the reagent from the less hindered backside. Acetolysis of that intermediate gives 16a-acetoxyestrone (30-3). Reaction of that product with lithium aluminum hydride leads to reduction of the 17-carbonyl and also the phenolic ester to give the trans-Aio 16a-hydroxy- 17(3-estradiol (30-4). The same product is obtained on reducing 30-2 directly also with lithium aluminum hydride. 

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... 

Scheme 5.43 illustrates three applications of this methodology to total synthesis. The first exeunple is taken from Posner s synthesis of estrone and estradiol [211], the second from Posner s synthesis of methyl jasmonate [212], and the third from Holton s synthesis of aphidicolin [213]. The latter is particularly noteworthy in that two contiguous quaternary centers are created in the asymmetric addition with excellent selectivity. In the estrone synthesis, the chirality sense of the product is consistent with the nonchelate model, but the other two examples adhere to a chelate model. Note that the difference is the degree of substitution at the a-position of the enolate. 

J -3-Keto isomerase catalyzes the isomerization of J -3-ketosteroids to zl -3-ketosteroids by stereospecific transfer of a hydrogen atom from C(4) to C(6). There is considerable evidence that it is the 40- and 6/5-hydrogens that are involved and that the reaction proceeds via an enolic intermediate. A low resolution (6 A) crystal structure determination has been published and the probable steroid-binding site identified via a bound inhibitor, 4-acetoxy-mercuric estradiol. The results of a higher resolution study (2.5 A) combined with the results of NMR studies and analysis of activity of mutant forms of the enzyme have helped to further define the probable active site of the enzyme [64]. 

In the estradiol prodrug estradiol 3-benzoate 17-P-cyclooctenyl ether (EBCO), the phenolic hydroxyl group is masked as a benzoyl ester and the alcoholic 17-p-hydroxyl, as an enol ether derived from cyclooctanone (Fig. 33.17). Given orally to rats as a suspension in sesame oil, this derivative was active for 1 to 2 weeks because it was stored in body fat. 

Although C4 addition occurs with phenol complexes even for cases where C4 is substituted, in many cases, ortho addition is thermodynamically favored. In this scenario, the regiochemistry can be effectively controlled by adjusting reaction variables such as temperature, time, and catalyst [44]. Under basic conditions, the active form of the phenol complex is the phenoxide species, which can undergo reversible Michael reactions at C4 and C2, provided that the resulting enolate is not protonated. For instance, the addition of MVK to the osmium complexes of para-cresol (31) or estradiol (27, Fig. 8) occurs at C4 to give the 4H-phenol product (28,32) at -40 °C with an amine base. However, if the reaction is carried out at 20 °C or is run in the presence of a Zn " co-catalyst, the initially formed enolate may undergo retroaddition, and ultimately, the reaction yields the orthoalkylated product (30,33 see Fig. 8). Electrophilic addition at the ortho... 

The transformation of estradiol-17/3 to estriol has been postulated to proceed by dehydrogenation of estradiol to yield the enolic form of estrone followed by hydration to estriol (Fig. 20). Another hypothesis is that estrone is first oxidized to 16-ketoestrone and thence reduced to 16-keto-estradiol-17/8 and estriol. There is no experimental evidence in favor of... 

Acetyl bromide (AcBr) is apparently superior to AcCl as a catalyst for enol acetylation, based on a report that 17 -benzoyloxyestra-4,9(10)-dien-3-one is converted into estradiol 3-acetate-17-benzoate in higher yield at much lower temperature using AcBr rather than AcCl (87.5% yield with 1 2 AcBr Ac20, CH2CI2, rt, 1 h (eq 10) vs. 81.0% yield with 1 2 AcCl Ac20, A, 4.5 h).i ... 

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