B-Norsteroids

The most important routes to B-norsteroids involve oxidative fission of 5,6-double bonds to keto acids or keto aldehydes which are then closed to five-membered rings by condensation reactions. Three of the best oxidation methods are exemplified in the following examples chosen from the cholestane, androstane, and pregnane series. 

Sorm found that when cholesterol acetate (67) is oxidized by chromic acid in acetic acid-water at 55°, crystalline keto seco-acid (69) is obtained in 25-30 % yield from the mother liquors after removal of successive crops of 7-ketocholesterol acetate (68). Reaction of keto acid (69) with benzoyl chloride in pyridine gives a dehydration product, shown to be the )5-lactone 

Hydrolysis of the acetate (71) followed by Oppenauer oxidation gives B-norcholest-4-en-3-one in high yield. An analogous reaction sequence can be used to prepare B-norprogesterone and derivatives of B-nortestosterone from pregnenolone acetate and dehydroepiandrosterone acetate, respectively.  

Acid (69). To a well-stirred mixture of 108 g (0.232 mole) of cholesterol acetate and 1.2 liters of glacial acetic acid is added over a period of 2 hr, a solution of 70 g of chromium trioxide in 200 ml of 50 % glacial acetic acid. The reaction mixture is maintained at a temperature of 55°. Upon completion of the addition, the mixture is stirred for an additional 2 hr at 55°. Excess chromic acid is destroyed by addition of 60 ml of methanol, and then 800 ml of acetic acid is removed by distillation under reduced pressure at a bath temperature of 40°. The remaining liquid is diluted with 50 ml of water and allowed to stand for 12 hr. The crystalline 7-ketocholesterol acetate which separates is removed by filtration and washed with 80 % acetic acid to yield 33.3 g (35%) of (68) mp 149-152°. 

The filtrate is diluted with 140 ml of 50% methanol-water and placed in the refrigerator for 3 days. The thick sheet of crystalline material which forms on the surface is removed by filtration and washed with 75 % acetic acid to yield 32.5 g of crude product. The filtrate is again cooled overnight and an additional 8.7 g of solid is removed. The crops are combined and the material, mp 120-124°, which is highly colored due to chromium salts, is recrystallized twice from methanol to yield 27 g (24 %) of the keto acid (69) mp 127-129° 78° (CHCI3). 

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An alternative to fluorohydrin formation is observed with the 6/ -methyl-5a,6a-epoxide (30), which rearranges, possibly in a concerted reaction, to the A-homo-B-norsteroid (31) (cf, chapter 14, Vol. II). 

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

In the course of synthetic efforts aimed at obtaining 6j5-fluoro steroids, Kirk and Petrow treated a 3)5-acetoxy-6-raethyl-5a,6a-epoxide with boron trifluoride etherate and unexpectedly obtained a fluorine-free acetoxy ketone." Later transformations established that the product was the A-homo-B-norsteroid (104). 

High yields of A-homo-B-norsteroids are also obtained on rearrangement of the 5a,6a-epoxides from 3)3-hydroxy-6-methylandrost-5-en-17-one and Sp, 17)5-diacetoxy-6-methylandrost-5-ene. 

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

An excellent alternative route to 5,6-seco-acids of general structure (69) has been used by Knof to prepare B-norsteroids. Although the single-step chromium trioxide oxidation process described in section III-A is convenient when starting materials are readily available and relatively low yields are acceptable, the multistep Knof process may be preferred when high yields are important or when a sensitive functionality is present. 

In a typical Knof procedure, 3jS-hydroxyandrost-5-en-17-one acetate is epoxidized with perbenzoic acid (or m-chloroperbenzoic acid ) to a mixture of 5a,6a- and 5)5,6)5-epoxides (75) in 99 % yield. Subsequent oxidation with aqueous chromium trioxide in methyl ethyl ketone affords the 5a-hydroxy-6-ketone (76) in 89% yield. Baeyer-Villiger oxidation of the hydroxy ketone (76) with perbenzoic acid (or w-chloroperbenzoic acid ) gives keto acid (77) in 96% yield as a complex with benzoic acid. The benzoic acid can be removed by sublimation or, more conveniently, by treating the complex with benzoyl chloride and pyridine to give the easily isolated )5-lactone (70) in 40% yield. As described in section III-A, pyrolysis of j5-lactone (70) affords A -B-norsteroid (71). Knof used this reaction sequence to prepare 3)5-hydroxy-B-norandrost-5-en-17-one acetate, B-noran-... 

A-homo-B-nor-5/3-choIestan-4a-one, 394 A-homo-B-norsteroids, 389 B-homo-19-norsteroids, 379 B-homo-5a-pregnane-3, 20/3-diol diacetate, 376... 

V. 10(5 -> 6pH)Abeostero ds (A-Homo-B-Norsteroids) / 389 Solvolysis of 5a,6a-epoxy-6-methyl steroids / 389 Pinacol rearrangement of 5a-hydroxy-6a-tosylates / 392 Summary / 394... 

An approach to the synthesis of B-norsteroids involves -alkylation of dienamine 65 with m-methoxybenzyl bromide and ring closure with H3P04 and P2Os53 (Scheme 34). The use of 2-(m-methoxyphenyl)allyl bromide gave access to 6-methyl- 19-norsteroids54. 

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