Androstene oxide

Bacterial removal of sterol side chains is carried out by a stepwise P-oxidation, whereas the degradation of the perhydrocyclopentanophenanthrene nucleus is prevented by metaboHc inhibitors (54), chemical modification of the nucleus (55), or the use of bacterial mutants (11,56). P-Sitosterol [83-46-5] (10), a plant sterol, has been used as a raw material for the preparation of 4-androstene-3,17-dione [63-05-8] (13) and related compounds using selected mutants of the P-sitosterol-degrading bacteria (57) (Fig. 2). 

Oxandrolone Oxandrolone, 17j3-hydroxy-17a-methyl-2-oxa-5-androstan-3-one (29.3.10), is made by oxidation of the C1-C2 double bond of 17j3-hydroxy-17a-methyl-l-androsten-3-one by a mixture of lead tetraacetate and osmium tetroxide with an opening of the A ring of the steroid system, which forms an aldehyde acid (29.3.9). Upon reducing the aldehyde group with sodium borohydride, intramolecular cyclization takes place, directly forming a lactone (29.3.10), which is the desired oxandrolone [31,32]. 

Reactions catalyzed by 11 (3-hydroxysteroid and 17(3-hydroxysteroid dehydrogenases, (a) 11 (3-hydroxysteroid dehydrogenase type 1, an NADPH-dependent enzyme, catalyzes the conversion of the inactive steroid, cortisone, to cortisol, which is the biologically active glucocorticoid. 11 (3-hydroxysteroid dehydrogenase type 2, an NAD+-dependent enzyme, catalyzes the reverse direction, (b) 17(3-hydroxysteroid dehy-drogenase type 1, an NADPH-dependent enzyme, catalyzes the reduction of estrone to estradiol. Type 2, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone. Type 3, an NADPH-dependent enzyme, catalyzes the reduction of androstene dione to testosterone. Type 4, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone, and androstenediol to dehydroepiandrosterone. 

Initially, Moffatt et al. performed optimization studies on the oxidation of testosterone (14) to A4-androstene-3,17-dione (15).14... 

Degradation of the Side Chain of A4-Pregnene-ll, 17,20,21-tetrol-3-one (VIII) by Periodic Acid Oxidation.68 Small-Scale Oxidation. To a solution of 25 mg. of A4-pregHene-ll,17,20,21-tetrol-3-one in 1.5 cc. of methanol is added a solution of 40 mg. of periodic add in 0.3 cc. of water. After twenty hours the solution is diluted with water and freed from methanol in vacuum. The residue is extracted with ethyl acetate and ether. The extract is washed with water and sodium carbonate solution, and then dried over anhydrous sodium sulfate. The crystalline neutral product, obtained by evaporation of the solvent, is recrystallized from ether, then sublimed at 160° and 0.01 mm., and finally recrystallized from a mixture of ether and pentane. The yield of hygroscopic, fine needles of A4-androstene-ll-ol-3,17-dione (IX) melting at 189-191° (cor.) is 12 mg., or 60%. 

Whereas a,/ -unsaturated ketones afforded with DIB a-hydroxy-/ -methoxy dimethylacetal derivatives (Section 3.2.2), some steroidal ketones of this kind showed a deviation when treated with o-iodosylbenzoic acid for example, 4-androstene-3,17-dione gave a mixture of two methoxy derivatives and a diene [5]. Several sulphides were oxidized efficiently to sulphoxides by o-iodosylbenzoic acid in acetic acid-sulphuric acid, at room temperature [3]. o-Iodosylbenzoic acid is an excellent reagent for the rapid, catalytic cleavage of reactive esters, especially phosphates, some of which are in stock in big quantities for use as potential nerve gases. This kind of reactivity has drawn considerable attention, and several analogues of the parent acid showed better catalytic activity among them, a series of structurally interesting pyridinium 1,5-zwitterions should be mentioned [6] ... 

The 13,17-seco-acid lactone (258), obtained from a Baeyer-Villiger oxidation of 5a-androstan-17-one has been reduced to yield 13,17-seco-5a-androstan-13a,17-diol, whose diacetate on pyrolysis furnished the endocyclic seco-olefin (259 R = OAc) as the major reaction product. A minor product is the corresponding A12 13-olefin.115 Hydrolysis of the acetate (259 R = OAc) to its alcohol (259 R = OH) and formation of the tosylate and the iodide (259 R = I), followed by reaction with lithium dimethylcuprate, afforded a route to A1314-13,17-seco-5a-D-homoandrostene (259 R = Me). The [17a,17a,17a-[2H3]androstene (259 R = CD3) was prepared by treating the iodide (259 R = I) with lithium perdeuteriodimethyl-cuprate. 

The early functional models for this oxidation chemistry were rather simple Udenfriend used iron(II), EDTA, ascorbic acid (as the reducing agent) and O2 to hydroxylate arenes, while Hamilton showed that the same system hydroxylates unactivated C—H bonds (e.g. androsten-3-ol-17-one is converted to androsten-3,7-diol-17-one). Mimoun developed the use of an iron(II)/PhNHNHPh/ H1CO2H/O2 system which is also active for alkane hydroxylation. Curiously, other metals [copperfll), manganese(II), vanadium(II), cobalt(II)] are also active. In the hydroxylation of arenes, an arene oxide is believed to be the intermediate in P-450 dependent systems, because a 1,2-shift of a proton in the arene, the NIH shift is often observed. Neither the Udenfriend nor Mimoun models show such a shift, however. 

In an example of the use of this activation method testosterone, with a IT -hydroxy group, was oxidized to A -androstene-3,17-dione very rapidly in high yield, in contrast to the use DMSO-acetic anhydride. During a reaction, when other oxidizing agents were found to be ineffective, sulfur trioxide/dimethyl sulfoxide led to smooth oxidation of the df-diol (16 equation 8) to an o-quinone in 49% yield and the ci.r-diol (17) to (18 equation 9) in 98% yield. - The use of dimethyl sulfoxide-acetic anhydride for this oxidation gave large amounts of the diacetate as the by-product. 

A reagent suitable for oxidations of steroidal hydroxy ketones to diketones is dimethyl sulfoxide in the presence of various activators. It converts testosterone into 4-androstene-3,17-dione in 95-100% yields (equation 445) [1016, 1018],... 

For the formation of testosterone (51), androsten-5-3-ol-17-one (50) obtained by oxidation from cholesterol was employed although it was also derivable from diosgenin by way of l6-dehydropregnenolone as described for the preparation of progesterone. The synthesis of the androgen followed the route shown and the acetate was isolated in an overall yield of nearly 40% in the Syntex procedure from the androstenone intermediate. 

A5 - A 7-Steroid. Dauben and Fullerton chose the following route for conversion of A5-androstene-3/ ,l 7/5-diol diacetate (1) into A5 7-androstadiene-3/ , 17/3-diol diacetate (4). The starting material was converted into the 7-ketone (2) by oxidation with chromium trioxide-pyridine complex in methylene chloride (2,74-75). The ketone... 

Knof found this solvent superior to acetic acid for chromic acid oxidation of a mixture of the a- and )3-epoxides obtained from 3/3-acetoxy-A -androstene-l7-one. 

Dimethyl sulfoxide-Sulfur trioxide [1, 309, before references]. The combination of DMSO and sulfur trioxide, in the form of the pyridine complex, in the presence of trimethylamine oxidizes primary and secondary alcohols in good yield to aldehydes and ketones, respectively.55 The reaction usually is complete within minutes and the products are isolated by acidification and precipitation with water. The reagent also oxidizes allylic alcohols to the corresponding a,fi-unsaturated carbonyl compounds. One advantage over the DMSO-DCC method is that the elaborate purification required when dicyclohexylurea is a product can be dispensed with. Testosterone, with a 17/3-hydroxyl group, was oxidized toA -androstene-3,17-dione very rapidly the 17-epimer required a period of 35 min. 

Mit Pyridiniumchlorochromat gclingt die Oxidation von 3/L Acetox y-17/j - h y droxy- 17a-vinyl-5-androsten ... 

---