Steroidal ketols

Active metals readily cleave a-ketols and a-ketol acetates. Reductions can be carried out with the aid of lithium, barium or calcium in ammonia, or with zinc or tin, which are usually used in acidic media. Zinc is a relatively mild reducing agent and is therefore somewhat selective. Axial steroidal ketol acetates are reduced more readily than equatorial (equations 16 and 17). On the other hand, metal-ammonia systems are powerful reductants thus, calcium and barium reduce axial and equatorial isomeric ketol acetates with equal ease. Lithium is a more powerful reductant and frequently overreduces a-ketols... 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

REDUCTIONS OF STEROIDS BY METAL-AMMONIA SOLUTIONS / 45 3, Reduction of Ketol Acetates... 

J. E. StaiT, Metal Ammonia Reductions of Steroidal Enones, Saturated Ketones, and Ketols in Steroid Reactions, C. Djerassi, ed., Holden-Day, Inc., San Francisco, 1963, Chapter 7. 

A solution of bismuth trioxide in hot glacial acetic acid provides a specific method for the oxidation of acyloins. " The reaction rate is dependent on the steric accessibility of the ketol system. A 2,3-ketol requires less than one hour for completion but an 11,12-ketol is not yet fully oxidized in thirty hours." The reaction is highly selective as a-keto acids, hydrazines and phenols are not oxidized. In a direct comparison with cupric acetate, this procedure is somewhat superior for the preparation of a 2,3-diketone from a 2-keto-3-hydroxy steroid. ... 

The oxidation of the a-ketol moiety present in the steroid under examination and the subsequent reduction of triphenyltetrazolium chloride to the corresponding triphenylformazan are depicted in the following reaction ... 

For steroidal ketones and a-ketols, stereoselective cathodic reductions have been described [343]. The stereoselective reductive ring opening of epoxyketones to a ke-toalcohol has been used in the conversion of the corresponding steroids [344, 345]. 

Reactions based on the presence of the 21-hydroxy-20-keto functionality (ketol group) are much more specifie for corticosteroids, and these methods have been used for the determination of corticosteroids in pharmaceutical formulations or in biological fluids [72]. For instance, only 21-unesterified corticosteroids react with sodium molybdate in acetic acid medium [81]. The blue color obtained by reducing the ketol group allows the determination of 40-200 pg of these steroids. 

W P Schneider and A V McIntosh, U S Patent 2,769,824 (1957) [C A 51, 8822e (1957)] The use of NMO in catalytic Os04 reactions was first disclosed in this patent during work to introduce the corticoid side chain (an a-ketol) in a steroid... 

Most of the compounds that had been reported (before March, 1942) to show cleavage oxidation by periodic acid are recorded in the table the substances are listed alphabetically in the following groups of related compounds (1) carbocyclic compounds (2) carbohydrates (3) a-diketones and a-ketols (4) hydroxyamino compounds (5) polyhydroxy and hydroxyketo acids (6) polyhydroxy alcohols (7) steroids (8) miscellaneous compounds. French journals after May, 1940, and the majority of other foreign publications after June, 1941, were unavailable for the survey. 

Generally speaking the classical alkaline hydrolysis reaction followed by back-titration could be used to determine steroid esters. The results for 21-acyloxycortico-steroids (where R = H, OH) are however quite unsatisfactory. The reason behind the unacceptable result is the auto-oxidation of the a-ketol side-chain in an alkaline medium. Because of the formation of acidic products in side reactions, there is an over consumption of base in the titration and a corresponding over determination of the amount of steroid. 

A steroidal ketoenamine was reduced by an excess of NaBH4 to the corresponding 3/ -amino-4/ -ol derivative136. Other reducing agents [LiAl(OBu-03, B(NMe3)3, HCOOH, Raney Ni] were unsuccessful. Reduction with LiAlH4 afforded mixtures of a-ketols (Scheme 101). 

Several examples are known of the contraction of steroid rings by benzilic acid rearrangements of a -diketones [2g2]. Acyloin rearrangements in the steroid field, particularly in the conversion of i7-hydroxypregnan-20 ones into D-homo-ketols,... 

It appears possible that initial formation of the reduced complex (188) could lead, during hydrolysis, to the ene-diol (189) and finally to the ketol mixture. Ethylene-acetals of some oxo-steroids are reduced by lithium aluminium hydride-aluminium chloride to give 2 -hydroxyethyl ethers. 

A 23-bromocholan-24-al (291) affords the rearranged ketol (292) on hydrolysis with bicarbonate, but stronger alkali causes absorption of oxygen to give the a -hydroxy-acids (293), isolated as their esters.A remarkable feature is that 90% of this product mixture possesses the HR configuration, the reaction presumably being influenced asymmetrically by hindrance from the remainder of the steroid molecule. 

J. K. Norymbcrski. J. Chem, Soc. 1954, 762-4. Optical rotation steroid a-ketols, effect of internal H bond. 

O, y6-Unsaturated ketones of the structure RR C=CHCOCH3 yield on treatment with sodium amalgam a mixture of products, including tetrahydrofurans (V) and dihydrofuran derivatives (VI), glycols (VII), e-diketones (VIII), and ketols (XI) [85-87]. The ratio between the products depends on R and R bulky groups as found in steroids favor formation of glycols rather than of e-diketones [88]. The reactions leading to these products are similar to those discussed in Chapter 10. 

Acetates of a-ketols or their vinylogs are subject to reductive elimination of the acetoxy group by treatment with zinc dust and acetic acid. Thus both 6a- and 6/3-acetoxy-A -cholestene-3-one (16) are reduced smoothly to A -cholestene-B-one (17) the free alcohols are reduced somewhat less smoothly." In the case of steroidal... 

Tetrazolium Blue, in modifications of the original method for a-ketol steroids by Mader and Buck, is perhaps the most widely used. ... 

Lipides, 238, 239, 241-243, 261 Lipidosis, 239, 242, 243 Lobry de Bruyn-Alberda van Ekenstein transformation, 63, 291 acid catalysis of, 79 aldolization in, 77 base catalysis of, 79-81 catalysis of, by metal ions, 81 dealdolization in, 77 dehydration reactions in, 73 enzyme-catalyzed, 66, 70 formation of reductones in, 79 of or-hydroxy aldehydes, 71 mechanism of, 84 of noncarbohydrate a-ketols, 71 non-enzymic, 66, 67, 83 in paper chromatography, 81 rearrangement of carbon chain, 79 scope of, 65 of steroids, 72 use of, for synthesis, 82 Lyxonic acid, 3-deoxy-D-, 300 Lyxose, D-, condensation of, with urea, 218... 

Fig. 4. Part of a 20 X 20 cm thin-layer chromatography plate for the assay in urine of B, THS C, allo-THE E, THE F, allo-THP G, THF. Standard compounds have been run in positions 2, 4, 6, and 8. Cortisol is shown in position D and is measurable only if present in abnormally increased amount. The compounds shown in position A are mainly Cm steroids with an a-ketol group. Duplicate extracts from normal adult urines have been run in positions 1 and 3 from a case of adrenal carcinoma in position S from a normal infant in position 7 and from an infant with adrenogenital syndrome in position 9. The plate was sprayed with blue tetrazolium reagent, then heated. From Shackleton et al. (SIO).

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