Estrone enol acetate

Reaction of estrone enol acetate with phenylselenenyl or methylselenenyl bromide in the presence of potassium carbonate affords 16a-(phenylseleno)- or 16a-(methylseleno)estrone derivatives l17. 

Under similar conditions, the enol acetate and the trimethylsilyl ether of estrone were fluorinated to give the corresponding a-fluoro carbonyl compound (Fig. 54) [135]. 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

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. 

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