Preparation of 19-norsteroids

Selected examples for specific reactions sequences which will illustrate possible combinations for the preparation of 19-norsteroids via 19-functional-ized intermediates are given below. 

Preparation of lO-cyano-19-norpregn-5-ene-3/3,20 -diol diacetate, 270 Preparation of 19-norsteroids from 19-... 

Preparation of 19-norsteroids from 19-substituted steroids by solvolytic cleavage... 

Preparation of 19-norsteroids from 19-substituted steroids by transformations of 6/3, 19-ethers reductive cleavage of 5o -bromo-6/3,19-ethers, 266... 

III. Preparation of 19-Norsteroids from 19-Substituted Steroids / 264 Transformations of 6(3, 19-ethers / 264 Transformation of 19-oximino derivatives / 268 Removal of the C-10 substituent / 272 Summary and procedures for 19-norsteroids / 278... 

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. 

A new angular methylation procedure, at Cis, involving the Simmons-Smith reagent was discovered, thus extending the usefulness of the Smith-Torgov total synthesis of 19-norsteroids. The preparation and properties of 5,19-cyclosteroids was the subject of several studies.Interestingly enough, the Villsmeier reaction on enamines of 3-heto-A -steroids led to the 1,6-diformyl derivatives. ... 

A promising general method for preparing B-homo-19-norsteroids has been reported by Tadanier and Cole in a study of the horaallylic rearrangements of 19-substituted-A -steroids. The ready availability of 19-hydroxy-A -steroids cf. ehapter 12) makes this approach particularly attractive. 

The best chemical and optical yields in the above reactions are obtained by using (S)- or (R)-proline. Some 19-norsteroids are prepared on an industrial scale from products of intramolecular aldol additions catalyzed by (S)-proline 68). 

The Danishefsky group reported the use of an organocatalytic intramolecular aldol reaction in the synthesis of a key intermediate, 108, for preparation of optically active estrone and commercially relevant 19-norsteroids [118, 119]. In the presence... 

While most reactions with FC103 were performed on very electron-rich sites such as anions, it was also successfully reacted with enamines and vinyl ethers. Caspi and coworkers used this reagent to prepare 4-fluoroestradiols 24 from 19-norsteroid enamines (equation 133)235 while Garland and coworkers reacted it with enol ethers to produce eventually fluoroprostacyclins (equation 134) some of which possess profound biological effects236. 

Estrone, a key intermediate in the preparation of medicinally useful 19-norsteroids, can now be prepared in high yield at the remarkably low temperature of 35° from A -androstadiene-3,17-dione 17-ethyleneketal (1) by reaction with lithium-diphenyl in THF in the presence of a suitably acidic hydrocarbon such as diphenyl-methane to intercept the by-product methyllithium and prevent its addition to the potential 17-carbonyl group. ... 

The formation of pyridone products can be accomplished by the use of acetylenic esters. Aza-annulation of 198 with 57 resulted in the formation of 199 (eq. 43).27-68 Compound 199 was converted to 200, which was a key intermediate in the preparation of 4-aza-19-norsteroids. Reaction of 57 with hydrazine enamine 201 gave 202 which allowed access to the aromatized derivative 203 (eq. 44).69 Similarly, annulation of hydrazine enamine 204 with 205 resulted in formation of pyridone 206, which had a -CC Me substituent P to the lactam carbonyl (eq. 45).69... 

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