18- methyl-19-norsteroid

In at least one other company the increased price of diosgenin stimulated the research to achieve a total chemical synthesis of the steroid nucleus. This strategy has some advantages, one of which is that it makes available compounds based on the 18-methyl-19-norsteroid nucleus, such as nor-gestrol (26), which cannot be prepared from a natural product. As part of the synthetic process, which is a convergent one (Scheme 6.6), the prochiral cyclopenta-l,3-diones can be selectively reduced either by Rhizopus arrhizus or by Saccharomyces uvarum. There are also chemical strategies which will close the C-ring of the steroid with the correct stereochemistry at C-17. 

The 1950s and 1960s saw the development of orally active progestins based on the synthesis of steroids that lack the C19-angular methyl substituent (19-norsteroids). The commercial production of these compounds for the regulation of menstmal disorders began in 1957, and for oral contraception in 1960. 

Interest in the synthesis of 19-norsteroids as orally active progestins prompted efforts to remove the C19 angular methyl substituent of readily available steroid precursors. Industrial applications include the direct conversion of androsta-l,4-diene-3,17-dione [897-06-3] (92) to estrone [53-16-7] (26) by thermolysis in mineral oil at about 500°C (136), and reductive elimination of the angular methyl group of the 17-ketal of the dione [2398-63-2] (93) with lithium biphenyl radical anion to form the 17-ketal of estrone [900-83-4] (94) (137). 

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). 

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). 

SELECTIVE FUNCTIONALIZATION OF THE ANGULAR METHYL GROUP AND FURTHER TRANSFORMATION TO 19-NORSTEROIDS... 

The other three methods have not been studied extensively. The dimethyl-cadmium route has been used on a 17a-methyl-17 -carboxylic acid. ° The reaction of the acid amide with a Grignard reagent is described only in a Spanish patent,with a high yield claimed, and the methyllithium reaction has apparently been tried only on D-norsteroids. ... 

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-... 

In systems which preclude retro-aldol condensations, benzilic acid rearrangement of 11,12-diketones affords normal C-norsteroids in fair yields. For example, 11,12-diketotigogenin (82) is converted to the C-nor-(5oc,9(, 22a)-spirostane (83) in 65 % yield by barium oxide in boiling aqueous methyl-cellosolve. ... 

Epoxide (88) is converted to C-norpregnane (89) in 60% yield by methyl-magnesium iodide in refluxing ether-benzene. No rearrangement to the C-norsteroid occurs with dimethylmagnesium. 

During 1961-2 four independent groups almost simultaneously reported the first syntheses of D-norsteroids, based on the photolysis of 16-diazo-17-ketones. In a typical procedure. Cava and Moroz ° convert the 16-oximino-17-one (93) derived from estrone methyl ether (92) to the diazoketone (94)... 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

Scheme 34 Possible mechanism for the formation of 16a- and 16P-hydroxy-17P-methyl-A13-18-norsteroids...

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... 

In the course of synthetic efforts aimed at obtaining 6/J-fluoro steroids, Kirk and Petrow treated a 3/ -acetoxy-6-methyl-5a,6a-epoxide with boron trifluoride etherate and unexpectedly obtained a fluorine-free acetoxy ketone.48 Later transformations established that the product was the A-homo-B-norsteroid (104). 

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. 

Microbial hydroxylations at most positions in the steroid nucleus 1 are known, including 10j6-hydroxylation of 19-norsteroids, 14j8-hydroxylation of synthetic 14/i-steroids and 3-hy-droxylation of 3-deoxysteroids. In addition, hydroxylations of both angular methyl groups and of side-chain positions have been reported. 

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