19-Norandrostanes

Introduction of a la-methyl group in the moderately potent androgen, 19-norandrostan-17/3-ol-3-one, eliminates androgenic activity. 

The use of anisoles (22) as synthetic equivalents to cyclohex-2-enones (Scheme 3) has been widespread since the original observations of Birch, and the literature is replete with examples over the past five decades, e.g. in the syntheses of steroids, terpenoids and alkaloids. The most thorough studies have been carried out within the context of the conversion of estrone derivatives to 19-norandrostane and pregnane derivatives and are instructive for the selection of reagents and reaction parameters for reductions of this general type. ... 

A soln. of 500 mg. 5, 10 -oxido-19-norandrostane-3,17-dione in a mixture of acetone and benzyl mercaptan treated with some coned. HGl, and refluxed 1 hr. 

Total syntheses of steroids by this method of building up the skeleton have been used mainly to obtain estrogenic hormones and highly unsaturated derivatives of 19-norandrostane. These syntheses can be divided into two main groups. In the first of them, the AB and D moieties are linked initially by the formation of a C3-C14 bond, and in the second by the formation of a C12—C13 bond. Here the 11 and C12 atoms may be introduced either with the AB or with the D moiety or else, finally, be introduced into the finished tricyclic ABD intermediate. There are also variants of the synthesis in which the D ring is formed from acyclic precursors and is not introduced in finished form. In this section, syntheses of aza-, oxa-, and thia-analogs of steroid compounds are considered separately. 

From the D-homoestrapentaene (364) have been carried out the syntheses, on the one hand, of derivatives of estrone and D-homoestrone [454, 458, 460, 464-467], and, on the other hand, of 19-norandrostanes [141,... 

The Birch reduction of the methyl ether of rfZ-estradiol (407) has permitted the preparation of 19-nortestosterone (406), also synthesized independently from the -dehydro derivative (404). In the second case, however, the reduction of the A )-bond takes place nonselectively and with the (406) is formed its 9j8, lOa-isomer, amounting to about l/3 of the mixture of products. The third variant of the synthesis, from the A ( )-ketone (403), proved to be the most suitable, enabling (406) to be obtained in a single stage with an over-all yield of 55% [95, 489, 496]. Passage to derivatives of 19-norandrostane has also been effected by the Birch reduction of the ketals (393) and (401) [95,496] of the 17o -alkyl derivatives obtained from the ketone (403) and its 13-alkyl homologs [442, 488, 503, 504, 518-520] and also of the methyl ether of 8-isoestrone (368) and its 17 -dihydro and 13-alkyl derivatives. J... 

See also [K. K. Pivnitsky, N. N. Gaidamovich, and I. V. Torgov, Tetrahedron, 22 2837 (1966)]. tHeating the trienedione (419) with isopropenyl acetate leads to the acetate of A ( -de-hydroestrone (I) (yield 20%) from which the synthesis of a series of 19-norandrostanes with various degrees of unsaturation has been achieved. These syntheses confirmed, in particular, the location of the double bond in the A -position in compound (377) (see Scheme 36) and its D5-analog [L. Re, D. B. R. Johnston, D. Taub, and T. B. Windholz, Steroids, 8 365 (1966)]. 

The use in the reaction illustrated in Scheme 54 of 2-alkyl derivatives of 1,3-cyclopentanedione enabled analogs of estrone containing alkyl groups other than methyl (Et, Pr, i-Pr, Bu, i-Bu, i-Am, cetyl, etc.) in position 13 to be obtained. The resolution of (133) and its 13-alkyl homologs into enantiomers has been carried out by both chemical and microbiological methods both series of enantiomers have been reduced by Birch s method to derivatives of 19-norandrostane [442, 488, 619]. ... 

Masse, R., Lahberte, C., and Tremblay, L. (1985) Gas chromatography-mass spectrometry of epimeric 19-norandrostan-3-ol-17-ones as the trimethylsilyl ether, methoxime-trimethylsilyl ether and trimethylsilyl-enol trimethylsilyl derivatives. Journal of Chromatography, 339,11-23. 

In the one application reported for the conversion of the 17jff-acetyl side-chain to the 17-ketone, the intermediate oxime was not isolated, but hydrolyzed in situ with acid in an overall yield of about 20 %. In the case of 17jff-acetyl-D-norandrostanes, which are particularly difficult to degrade to D-norandrostanes, the nitrite procedure proved the most convenient method. The yield is 25 %, nowhere near the much higher yield obtained by a Baeyer-Villiger reaction which, however, must be allowed to proceed for one month at 0°. ... 

The cyanogen azide-enamine ring contraction procedure has also been used to prepare an A-dinorsteroid (16) from 17j5-acetoxy-A-norandrostan-2-one (15). " ... 

Diketo steroids have been prepared by air oxidation of 3-keto-5i5-steroids in potassium /-butoxide-t-butanoF or by hydrolysis of 4,5-epoxy-3-ketones followed by dehydration. However, the most general synthesis is that used by Camerino et al. to prepare Vketo-A-norandrostanes and pregnanes. Hydroxylation of 17a,20.20,21-bismethylenedioxypregn-... 

Hydroxy-5-oxo-3,5-seco-4-norandrostane-3-carboxylic acid has been prepared by ozonolysis of testosterone2-4 or of testosterone acetate, followed by alkaline hydrolysis,5 and by the oxidation of testosterone acetate with ruthenium tetroxide.9... 

Nonynoic acid, methyl ester, 55, 76 S ECCM-NORANDROSTANE-B-CAR-BOXYLIC ACID, 17(3-hydroxy-5-oxo-, 55,67... 

An intermediate (21a) that might be useful in the synthesis of samandarine (22) has been prepared from the A-norandrostane derivative (21b).13 Full details... 

Application of the Beckmann cleavage route to the preparation of 18-norandrostan-17-ones185 (219) has been improved by intermediate formation of the 13-carboxy-13,17-seco-nitriles (217), which cyclized with base to form the 13a- and 13/3-isomers of the a-cyano-ketone (218) and thence the 18-nor-13a- and -13/3-androstan-17-ones (219).186 A similar reaction sequence has been employed for... 

The syntheses and biological activity of ring-A heterocyclic steroids have been reviewed. The JV-cyano-2-aza-A-norandrostane (333) was synthesized from the dibromo-seco-compound (331) via the JV-phenyl-2-aza-A-norandrostane (332) (Scheme 17). The mixture of iodoisothiocyanates (334) and (335) (see ref. 

Reaction of 17/J-acetoxy-la,2oc-epoxy-lj3-methyl-5a-androstan-3-one (224) with acid gave an isomeric mixture of A-nor-2-oxo-steroids (225) carrying a formyl group at C(l). Treatment of this mixture with base provided exclusively the l/ -methyl-A-nor-steroid (226).The 3a-methyl-A-norandrostane derivative (230) has been prepared as shown in Scheme 16, i.e. by oxidative cleavage of ring A of the 3-keto-derivative (227) followed by Dieckmann condensation of the diester (228), and methylation and decarboxylation of (229). - ... 

Fusidic acid has been degraded to adrenocortical hormone analogs and to derivatives of iK2,8a,lUp-trimethyl-l8-norandrostane. The structxure of Withaferin A has been confirmed by degradation to bisnor-5Ct-cholanic acid. ... 

A-norandrostanes having lOa-amino-alkyl substituents have been prepared and shown to possess some antibacterial activity. 

An improved degradation of methyl fusidate (325) to the 14/3-methyl-18-norandrostane (328) has been described (Scheme 16). Evidence was presented that the conversion of the lla-acetoxy-compound (326) into the A -compound... 

A soln. of 2.57 g. ll, 17/ -dihydroxy-5-oxo-3,5-jeco-A-norandrostan-3-oic acid f-lactone 17-acetate in dioxane-water irradiated 7.5 hrs. at 25-30° with a 200 w. high-pressure Hg-lamp 0.761 g. 9 -acetoxydodecahydro-5,9ay -dimethyl-2-oxo-2H-indeno[5,6-b]oxepine-6a-propionic acid. W. Koch, M. Carson, and R. W. Kier-stead, J. Org, Chem. 33, 1272 (1968). 

Azasteroids. Thionyl chloride added to a soln. of 400 mg 13 -benzylamino-13,16 Seco-5a-17-norandrostane-3jd,16-diol in dioxane, and allowed to stand 1 hr. 

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