307. Compounds related to the steroid hormones. Part IX. Oxygenation of steroid ketones in strongly basic medium: a new method of preparation of 17α-hydroxypregnan-20-ones

Abstract

20-Oxo-steroids, in presence of a t-alkoxide in the corresponding alcohol, react with oxygen to give the 17a-hydroperoxy-20-ketone in fair yield; reduction, best with zinc and acetic acid, then gives the 17a-hydroxy-20-ketone. The speed of hydroperoxidation is notably affected by the nature of the substituents at C(,,j and in ring c. In the same way, a 6-oxo-5a-steroid is converted, via the fia-hydroperoxy-derivative, into the 5a-hydroxy-6-ketone. 3-0xo-5a-and 12-oxo-steroids, on the other hand, are oxidised to the 2 3and 11,12-dioxo-compounds respectively.KETONES react rather sluggishly with oxygen, and the products are usually those resulting from cleavage of the carbon chain adjacent to the carbonyl group; the a-hydroperoxyketone has been postulated as an intermediate, and such a compound has been isolated, along with its decomposition products, from the oxidation of di-isopropyl ketone at However, when a ketone forms a stable enol, the latter (but not the ketonic form), in solution in ether, light petroleum, or benzene, reacts readily with oxygen at ordinary temperature to give the a-hydroperoxy-ketone, which, under these mild conditions, is easily isolated ; 4*5 even secondary a-hydroperoxy-ketones have been prepared in this way, in spite of the ease with which they are dehydrated to a-diketones6Most simple ketones exist to a negligible extent in their enolic forms under neutral conditions, but enolisation is favoured by basic or acidic conditions. However, although several workers have shown that, in strongly basic medium, ketones w i l l take up oxygen rapidly at ordinary temperature, they have, again, usually isolated cleavage products ; this is readily explained by the initial formation of the a-hydroperoxy-ketone, for such compounds are known to be cleaved by base.' That autoxidation of ketones can proceed without cleavage of the carbon chain is indicated by the conversion of +unsaturated ketones of the cyperone series into their y-hydroxy-derivatives by oxygenation in presence of aqueous base8 and by the recent observation that certain rotenone derivatives give a-ketols under similar conditions? It seems probable that the hydroperoxy-ketones are intermediates in such oxidations, since there are analogies for the " reduction " of such compounds to the ketols by dilute alkali.u*c More important, for the present purpose, was the observation that, even under strongly basic conditions, the reaction can leave the carbon chain intact. Thus, cyclic ketones of type (I), in the limonin series, react with oxygen in presence of potassium t-butoxide in

Identification of several Tonalide® transformation products in the environment

“…The reaction products were characterised by 1 H-NMR, 13 Karlsruhe, Germany). The solvent and internal reference is given for each spectrum.…”

Base-catalyzed protium–deuterium exchange in bicyclo[2.2.1]heptanones

“…In dione !_, this is also possible, 14 via horroenolic particip3.tion* of the second carbonyl, as in structure 8. That such horroenolic p3.rticip3.tion is p::>ssible is illustrata:l 6 7 8 by the fact that it may have been detecta:l before in the reactions of phosphines with 4-trihalomethylcyclohexa-2,5-dien-1-ones (9):…”

“…'Ihe mechanism of the reaction has been postllla ted 1 4 to be as shown in Schane I -4. _ 'lhe fonnation of the a-hydroperoxyketone ~ is thought to go through the rrechanism depicta:l in Scheme I-5: 8 Step from! to 2_ ma.y consist of the radical chain process depicta:l in Scheme I-6.…”

“…heptanones had reen reported, and this further prompted our kinetic studies. Thomas and Willhalm 2 8 exdl.anged isofenchone (12) in dioxane-D 2 0-NaOD solutions for 3 days at room temperature, and obtained a nonodeuterated compound (97 % isotopic purity). The deuterium cOntent was not appreciably altered after a second exchange for 20 minutes at 90° • camphor (7.) and norcamphor ( 13) ¥.ere found to behave similar ly.…”

The Mechanism of The Microbial Hydroxylation of Steroids. Part 1. The C-21 Hydroxylation of Progesterone by Aspergillusniger ATCC 9142

“…The substrates most commonly used (1) for microbial hydroxylations have been A4-3-ketosteroids and it has been proposed (1) that, during their hydroxylation at C-2, -6, -17, or -21, activation occurs by enolization and that hydroxylation occurs by electrophilic attack of oxygen at the enol. This is shown for hydroxylation at C-21 of a C-20 ketosteroid in Scheme the facile oxidation by electrophilic oxygen of steroidal enols to a-hydroperoxy or a-hydroxy ketones (10)(11)(12)(13)(14) and by enzymic enolization of ketosteroids (15). Further evidence, albeit circumstantial, is provided by the frequent occurrence of hydroxylations of A4-3,20-diketosteroids at the axial 2P, 6P, lop (in 19-norsteroids), and 17a positions, whereas microbial hydroxylations at 2a, 6a, 10a, and 17P are unknown (1): analogously, electrophilic attack on the corresponding enols gives exclusively axial substitution of the electrophile (1 1-13, 16).…”