Estranes

The adventitious discovery of the antitumor action of the nitrogen mustard poison war gases led to intensive investigation of the mode of action of these compounds. In brief, it has been fairly well established that these agents owe their effect to the presence of the highly reactive bis(2-chloroethyl)amine group. The cytotoxic activity of 

Reaction of bis(2-chloroethyl)amine with phosgene affords the corresponding carbamoyl chloride Acylation 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group 

A rather more complex scheme is required for preparation of the analogue gestrinone (27) which contains 

The alkaloids are produced in skin glands and may protect against microbial infections (E 5.1). In addition they are poisonous to animals if ingested and may repel potential predators. 

Schreiber, K., Schiitte, H. R. Isoprenoid alkaloids. In Biochemistry of Alkaloids (K. Mothes, H. R. Schiitte, M. Luckner, eds.), Deutscher Verlag der Wissenschaften, Berlin 1985 

Habermehl, G. The biological significance of amphibian venoms. In Secondary Metabolism and Coevolution (M. Luckner, K. Mothes, L. Nover, eds.). Nova Acta Leopoldina, Suppl. 7, 499-502 (197(S) 

Estranes are steroid derivatives with an aromatic A ring. They are devoid of the angular methyl group at C-10. The ring system may be substituted by hydroxy or carbonyl groups. 

Estrone and estradiol are derived from testosterone (Fig. 131). Aromatization of ring A is catalyzed by a single enzyme (steroid aromatase), which mediates two 

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The preparation of estranes via 19-hydroxy steroids has also been accompHshed microbially. 19-Hydroxycholesterol, prepared chemically (39), is incubated with JS icardia restrictus to provide estrone (20) direcdy (44). Similarly, 19-hydroxyandrost-4-en-3,17-dione is converted to estrone (20) (45). 

Estranes. Investigations into the total synthesis of steroids began in the 1930s shordy after the precise formula for cholesterol was estabUshed. The eadiest studies focused on equilenin (5) because of its relative stereochemical simplicity when compared to other steroid nuclei Initially, equilenin was synthesi2ed in 20 chemical steps with an overall yield of 2.7%. This synthesis helped to confirm the perhydro-l,2-cyclopentenophenanthrene ring system of... 

Chemical Analysis. Chemically, the various progestogens belong to one of three classes. Estranes are 19-nortestosterone derivatives (Fig. 1) gonanes are 19-nortestosterone derivatives with a C-13 ethyl group (Fig. 2) and pregnanes are 17-alpha-OH progesterone derivatives similar in stmcture to progesterone itself. 

For the reduction of conjugated enones to saturated alcohols, Procedure 5 (section V) may be modified by adding methanol in place of ammonium chloride a sufficient excess of lithium is present to effect reduction of the intermediate saturated ketone to the alcohol. Procedure 2 (section V) for effecting Birch reductions is also useful for reduction of conjugated enones to saturated alcohols. Thus, 17-ethyl-19-nortestosterone affords crude 17a-ethyl-5a-estrane-3) ,17) -diol of mp 174-181°, reported mp 181-183°, in quantitative yield. 

The hydrogenation of ring A aromatic steroids over ruthenium occurs, almost invariably, from the a side and all substituents on the original aromatic ring are cis in the resulting cyclohexane. Estrone (62) is hydrogenated over ruthenium to 5a,10a-estrane-3/3,17j6-diol (63) in 85-90% yield. 

A solution of 20 g of estradiol in 500 ml of ethanol containing 1 ml of 40 % sodium hydroxide is hydrogenated over 5 g of ruthenium oxide or 3-5 g of 5% ruthenium-on-charcoal at 65° and 1500 psi. After filtration and evaporation, the residue is recrystallized to give 80% of 5a, 10a-estrane-3j9, 17 -diol. °... 

This sequence of steps has been used to prepare a large number of 6a-methyl-3-keto-A" -steroids in the estrane/ androstane " and preg-nane " " series. 

Hydroxy-4a ,5a-epoxy-17 a-methylan-drost-9( 11 )-en-3-one acetate, 315 17 -Hydroxy-4/3,5/3-epoxy-17a-methyl-estran-3-one, 314... 

Hydroxy-6-methyl-10 (5 6) abeo-cholestan-5-one acetate, 391 3 a-Hydroxy-16a-methyl-11,20-dioxo-5/3-pregnane-21-glyoxylic acid, 191 17 -Hydroxy-l-niethyl-A-homo-5a-androst-l-en-3-one acetate, 362 17 /3-Hy droxy-5a, 1 Oa-methy lene-A-norestran-3-one, 429 17 3-Hydroxy-17 a-methyl-10 ( 5 4) -fl( < o-estrane-3,5-dione, 314 3a-Hydroxy-16a-methyl-5/3-pregnane-11,20-dione, lyl... 

Hydroxy-5,10-seco-cholest-c/s-1(10)-en-5-one acetate, 397 3 -Hydroxy-5 (10) -seco-cholest-tra -1 (10)-en-5-one acetate, 397 17 -Hydroxy-5,10- eco-estrane-3,5,10-trione acetate, 395... 

Contraceptives. Figure 3 Examples of progestins derived from progesterone (pregnanes), 19-nortestosterone (estranes), and norgestrel (gonanes). 

Estrogens are 18-carbon steroids based on the estrane nucleus. In the non-pregnant female, they are mainly produced in the ovary. 

Figure 42-3. Cholesterol side-chain cleavage and basic steroid hormone structures. The basic sterol rings are identified by the letters A-D. The carbon atoms are numbered 1-21 starting with the A ring. Note that the estrane group has 18 carbons (Cl 8), etc.

The prototype for the estrane series is the female sex hormone estradiol (1 ). Estrogens have important... 

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