Saturated Ketosteroids

The sulfates of saturated ketosteroids are readily split under the conditions of acid hydrolysis described above (Section III,1) which were found effective for the cleavage of glucosiduronates. However, their cleavage may also be accomplished under very much milder conditions, as was shown by Lieberman and Dobriner (79) and subsequently confirmed by Buehler et at. (14) (Table III, method A). Continuous extraction with ether at pH 0.7 for 24 to 48 hours gives a quantitative recovery of the free steroid. The hydrolysis of the sulfate esters takes place without inversion of stereochemical configuration (82). 

Lithium acetyhde also can be prepared directly in hquid ammonia from lithium metal or lithium amide and acetylene (134). In this form, the compound has been used in the preparation of -carotene and vitamin A (135), ethchlorvynol (136), and (7j--3-hexen-l-ol (leaf alcohol) (137). More recent synthetic processes involve preparing the lithium acetyhde in situ. Thus lithium diisopropylamide, prepared from //-butyUithium and the amine in THF at 0°C, is added to an acetylene-saturated solution of a ketosteroid to directly produce an ethynylated steroid (138). 

The absence of characteristic waves of the aldehydic group can, of course, be used as a proof of the absence of the group in a molecule. In this way, the absence of an aldehydic group has been proved (57) for absinthindiol, guajtriol C and artemazulene. The presence of a phenacyl group has been proved in the molecule of kynurenine (755). a,(3 unsatura-ted ketones can be distinguished from saturated ketones, e.g. A4-3-ketosteroids and A1 4-3-ketosteroids can be detected in the presence of 3-ketosteroids and can be even determined in a mixture (772). 

Six new 3p,5,6P-trihydroxysterols with a saturated nucleus have been isolated from two different populations of the sponge Cliona copiosa, collected from two different sites of the bay of Naples. Successively, several new D5-3p-hydroxy-7-ketosteroids and the related As-3p, 7p, and As-3p,7a-dihydroxysteroids have been described as constituent of the same species. 

A - iiml A" -3-kt loncs me iiol ad cclcd. However, iiiulei more viyorou.s eomlilions, such as refluxing in n- or. ver-amyl iilcohol. A -, A -. A "-, and saturated 3-kelo-steroids (7) are all converted into A - -3-ketosteroids (8). For these dehydrogenations chloranil is superior to other readily available quinones. Other examples. ... 

Dehydrogenation of carbonyl compounds. The reagent is useful for introduction into steroid ketones of double bonds that enhance biological activity. A saturated 3-ketosteroid (5) is dehydrogenated by DDQ in refluxing benzene or dioxane to the A -3-ketone (6). - A A -3-ketosteroid (7) can undergo dehydrogenation in two ways. 

Prepared from dimethylformamide diethyl ketal by transacetalization with ethylene glycol. In the presence of a catalytic amount of acetic acid, the reagent reacts selectively with saturated 3-ketosteroids to give the 3-ethyleneketal in the presence of other saturated or unsaturated keto functions. Under the mild conditions cited, A -3-ketosteroids and 12- and 20-ketosteroids do not react. 

A -3-Ketosteroids also afford A - -dienones in low yield. Harrison of Syntex found that, given sufficient reagent and purified solvents, both primary and secondary saturated alcohols can be oxidized in high yield, but slowly. Thus 100 mg. of 5a-androstane-17/8-01 stirred at room temperature in hexane or acetonitrile (20 ml.) OH... 

Diaziridines and diazirines [1,483]. A Lederle group13 investigated the reaction of hydroxylamine-O-sulfonic acid with steroid ketones and found that only noncon-jugated 2(5a)-ketones and 3(5a or 5/3)-ketones react. A4-3-Ketosteroids, 17-keto-steroids, and 20-ketosteroids were found unreactive. A solution of 502 mg. of 17a-methyl-5a-androstane-17/3-ol-3-one (1) in methanol was saturated with ammonia at 2° and treated with 236 mg. of hydroxylamine-O-sulfonic acid, added in small portions. The diaziridine (2) was oxidized with silver oxide in ether in practically quantitative yield to the diazirine (3). 

Hydroxylation. No hydroxylation at the 4-position has been reported. The usual substrates for microbial transformations are A -3-ketosteroids. The double bond at toe 4-position interferes with normal modes of hydroxylation, accounting for the bulk of toe experience to date. Saturated substrates might reasonably be hydrox-ylated at the 4-position with appropriate microorganisms. Substrates of the 3-keto-5 -pregnane series might be preferred since their normal mode of enolization is toward toe 4-position, thereby offerii the possibility of more than one mechanism of hydroxylation. 

In general, preferred substrates for 1-dehydrogenation are A -3-ketosteroids. Saturated 3-ketosteroids have also been used, but chemical methods of dehydrogenation are usually superior to microbial methods for these substrates. 

A more predictable approach to reduction, developed by Schubert, involves the anaerobic application of Clostridium paraputrificum to A -3-ketosteroids (Ap-71, S-823). In linstances (testosterone, progesterone, corticosterone, cortisone) the product is the correspondir 3a-hydroxy-5/3-steroid. From AL -3-ketosteroids the correspondii A -3a-hydroxy-5/3-steroid is formed in good yield, with a lesser amount of fully saturated hexahydrosteroid as a by-product. From AL. -3-keto-steroids or A > -3-ketosteroids the end-product of hydrogenation is the A -3o -hy-droxy-5/3-steroid. 

Normally the reaction of thiols with carbonyls, saturated or unsaturated, leads to the formation of dithioacetals when acid catalysts such as zinc chloride or p-toluene-sulphonic acid are present (see section II.A. 1). Occasionally, under special reaction conditions thioenol ethers have been formed using these same catalysts but never in the presence of acid-sensitive substituents. Pyridine hydrochloride as the catalyst has been successfully used to give excellent yields of the thioenol ethers of A -3-ketosteroids even in the presence of sensitive groups . Thus, desoxy-corticosterone acetate (92) was converted to its 3-benzylthioenol ether... 

The crude extracts contain, in addition to the ketosteroids, nonketonic, acidic, and phenolic material (estri ns) as well as pigments. The acidic material may be removed by washing with saturated sodium bicarbonate solution, the phenols by washing with normal sodium hydroxide solution, and the amount of pigment present in the extract may be reduced by washing with alkaline sodium dithionite solution. After removal of these undesired constituents of the crude extract, the ether or other organic solvent is distilled off, leaving behind the neutral fraction as residue. 

The isomerisation have already been reported. The formed diradical recombines, which gives rise to thermodynamically more stable isomer. The photochemical epimerisation of 17-ketosteroids and other mentioned saturated cyclic carbonyl compounds is through Norrish type I, a-cleavage. 

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