Substituents angular

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). 

Besides the aforementioned chemical methods, microbial degradations have been used to remove the C19 angular methyl substituent of readily available steroid precursors. For example, 19-hydroxysterols, such as 3P-acetoxy-19-hydroxy-5-cholestene [750-59-4] (107), can be converted to estrone by Mocardia sp. in yields up to 70% (120,145,146). 

However, the removal of the angular substituent can be made a very efficient process by first oxidizing the 19-hydroxyl to the aldehyde or acid stage. This procedure, first described by Haglwara" has since been applied to a large variety of 19-hydroxy steroids. 

Methylbenzotriazole derivatives with an aminoethylene substituent in position 4 also regioselectively produce only the angularly annelated 7-ethoxycarbonyl-6-0X0-6,9-dihydro-2-methyl-2//-triazolo[4,5-/i]quinoline 158. Under alkaline hydrolysis the ester 158 yielded the corresponding acid 159 (90CCC1038, 92FA1001). 

Steroids not readily accessible by modification of plant starting materials, for example, those possessing unusual substituents at the angular positions, are made available by total synthesis. 

Cyclopropanes are now readily available and have become useful, through hydrogenolysis, for synthesis of compounds containing quaternary carbons, em-dialkyl, r-butyl, and angular-methyl substituents (779), compounds often available only with difficulty otherwise (.77,5i,55,750,756), Cyclopropanes can be formed in good yields by hydrogenation of cyclopropenes (26). 

The 1,6-intramolecular addition of unsymmetrical allylsilanes to conjugated dienones proceeded to give a trans relation between the angular substituents and the vinyl groups (complete 1,3-asymmetric induction). Ethylaluminum dichloride has been most successfully used in all reactions described35-53. 

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