Removal of the C-10 substituent

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. 

Base-catalyzed fragmentation also occurs on treatment of 5,6j9-epoxy-19-aldehyde (hemiacetal, hemiacetal-acetate or 3)5,6/ -acetal) accessible from nitrous acid-acetic acid treatment of 5a-bromo-6jS-hydroxy-19-oximes followed by mild base hydrolysis (yield not reported) 

Androst-4-ene-3,17,19-trione (0.23g) is added to a precooled solution of 0.23 g of potassium hydroxide in a mixture of 1 ml of water and 5 ml of methanol. The reaction mixture is stirred at 5-10° under nitrogen for 3 hr, diluted with benzene (30 ml) and washed with water (2 x 10 ml). The aqueous layer is reextracted with benzene and the benzene solution dried and evaporated. The crude crystalline product is filtered through 8 g of Merck silicagel and eluted with benzene-ethyl acetate (9 1) to yield 0.19 g of 19-norandrostenedione (88%) mp 169-171° 141° (CHCI3). 

The formation of a A -3-keto-19-norsteroid from the A -3-keto-19-acid in hot pyridine solution was first reported by Hagiwara. The same product is also obtained from the j ,y-unsaturated acid under identical con- 

5(10)-Unsaturated 19-norsteroids are also obtained by thermal decarboxylation of A -19-acids (obtained by zinc reduction of the 5a-halo-6/3,19-lactones). 

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Rearrangement of a,/B-epoxy ketones to ftdicarbonyl isomers, 307 Reductive alkylation, 97 Reductive cleavage of halo ethers, 264 Reductive degradation of 19-substitutional steroids, 277, 278 Reformatsky reaction, 139 Removal of the C-10 substituent in steroids. 272... 

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... 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

The silyl group directs electrophiles to the substituted position. That is, it is an ipso-directing group. Because of the polarity of the carbon-silicon bond, the substituted position is relatively electron-rich. The ability of silicon substituents to stabilize carboca-tion character at )9-carbon atoms (see Section 6.10, p. 393) also promotes ipso substitution. The silicon substituent is easily removed from the c-complex by reaction with a nucleophile. The desilylation step probably occurs through a pentavalent silicon species ... 

The acidifying effect of the remaining acceptor substituents of Table 10.1 decreases in the order —C(=0)—H > —C(=0)—alkyl > —C(=0)—O-alkyl, and the amide group —C(=0)—NR2 is even less effective. This ordering essentially reflects substituent effects on the stability of the C=0 double bond in the respective C,H-acidic compound. The resonance stabilization of these C=0 double bonds drastically increases in the order R—C(=0)—H < R—C(=0)—alkyl < R—C(=0)—0—alkyl < R—C(=0)— NR2 (cf. Table 6.1 see Section 7.2.1 for a comparison between the C=0 double bonds in aldehydes and ketones).This resonance stabilization is lost completely once the a-H-atom has been removed by way of deprotonation and the respective enolate has formed. 

Bornane[10,2]sultams have been exploited as chiral auxiliaries for stereoselective aziridination of attached 7V-enoyl substituents28. The alkene substitution pattern markedly affected the diastereoselectivity, which was excellent when the C — C double bond was unsubstituted in this case the configuration of the prevalent diastereomer 5 was established by X-ray crystallographic analysis. Thus, the addition occurred to the Re-face at the a-carbon. In the other cases the stereochemistry of the major diastereomers was tentatively assigned by analogy. Furthermore, the yield dropped drastically when an a-substituent was present. Removal of the auxiliary was achieved by titanium isopropoxide alcoholysis, but was not optimized. No epimerization occurred during the cleavage process. 

The facts that inversion of configuration at C-9 is possible without abolishing the activity and that removal of the hydrogen (introduction of unsaturation between carbons 9 and 10) sometimes decreases (N-96) the androgenic and anabolic potencies and in many cases increases both potencies, point to the lack of importance of attachment to the receptor at carbon-9. Substitution of the 9-hydrogen by bulkier substituents usually decreases the activity but in the case of fluorine it increases it (S-19 and S-25). Removal of the 9-hydrogen and the simultaneous introduction of unsaturation between carbons 11 and 12 greatly enhances the activities. These facts also point to the uninvolvement of C-9 in the attachment to the receptor site. 

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