Oxidation of steroids

Acetone in conjunction with benzene as a solvent is widely employed. With cyclohexanone as the hydrogen acceptor, coupled with toluene or xylene as solvent, the use of higher reaction temperatures is possible and consequently the reaction time is considerably reduced furthermore, the excess of cyclohexanone can be easily separated from the reaction product by steam distillation. At least 0 25 mol of alkoxide per mol of alcohol is used however, since an excess of alkoxide has no detrimental effect 1 to 3 mols of aluminium alkoxide is recommended, particularly as water, either present in the reagents or formed during secondary reactions, will remove an equivalent quantity of the reagent. In the oxidation of steroids 50-200 mols of acetone or 10-20 mols of cyclohexanone are generally employed. 

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

The stereocontroUed syntheses of steroid side chains for ecdysone, cmstecdysone, brassinoHde, withanoHde, and vitamin D have been reviewed (185). Also, other manuscripts, including reviews on the partial synthesis of steroids (186), steroid dmgs (187—189), biologically active steroids (190), heterocychc steroids (191), vitamin D (192), novel oxidations of steroids (193), and template-directed functionali2ation of steroids (194), have been pubhshed. 

The oxidation of a hydroxyl group by an aluminum alkoxide-catalyzed hydrogen exchange with a receptor carbonyl compound is known as the Oppenauer oxidation. For oxidation of steroidal alcohols the reaction is generally... 

The nickel hydroxide electrode resembles in its applications and selectivity the chemical oxidant nickel peroxide. The nickel hydroxide electrode is, however, cheaper, easy to use and in scale-up, and produces no second streams/ waste- and by-products [196], Nickelhydroxide electrode has been applied to the oxidation of primary alcohols to acids or aldehydes, of secondary alcohols to ketones, as well as in the selective oxidation of steroid alcohols, cleavage of vicinal diols, in the oxidation of y-ketocarboxylic acids, of primary amines to nitriles, of 2,6-di-tert-butylphenol to 2,2, 6,6 -tetra-rert-butyldiphenoquinone, of 2-(benzylideneamino)-phenols to 2-phenyloxazols, of 1,1-dialkylhydrazines to tetraalkyltetrazenes. For details the reader is referred to Ref. [195]. 

SCHEME 125. Metal-catalyzed allylic oxidation of steroids with THBP... 

The above criteria apply in the case of isolated hydroxyl groups but when additional polar substituents are placed in the vicinity of the substrate hydroxyl the oxidation rate can be expected to change. Allylic hydroxyls are generally oxidized more rapidly than their saturated counterparts. Burstein and Rin-gold have studied the chromic acid oxidation of steroidal allylic alcohols in some detail and have found that the quasi-equatorial 3)3-isomer is oxidized more... 

Different reactivities of some substituted oxan-4-ols on oxidation by pyridinium chlorochromate (PCC) are rationalized on the basis of their conformational features, including twist conformations.2 A rate-determining carbon-carbon bond cleavage step in a glycol-PCC complex is proposed in the oxidation of butane-2,3-diol to acetaldehyde.3 Steroidal 6/i-hydroxy-4-en-3-onc was isolated as an intermediate in the oxidation of steroidal 5-en-3/i-ol with PCC.4... 

Oxidation of n-allylpalladiam chloride complexes. Snatzke s reagent is superior lo other chromium(VI) reagents for oxidation of steroidal tt-allylpalladium chloride complexes to a,/l-enones.1 Examples ... 

Breslow s template-directed remote oxidation of steroids utilizes an aryl iodide as a template to direct the oxidation of steroid tertiary carbons by the radical relay mechanism, in which a chlorine radical is transferred from a [9-1-2] [PhICl] radical to the iodine atom of the template and then relayed to a geometrically accessible hydrogen atom. This method allows a highly regioselective functionalization of nonactivated carbon atoms of steroids [Eq. (78)] [137,138]. 

Yang, J. Gabriele, B. Belvedere, S. Huang, Y., Breslow, R., (2002) Catalytic oxidations of steroid substrates by artificial cytochrome P450 enzymes J. Org. Chem. 67, 5057-5067. 

Oxidation of steroid enones3-Keto-A4-steroids are oxidized by blue tetrazolium (1) in an alkaline medium to 2,6-diketo-A4-steroids in 70-80% yield. Other examples ... 

Rather regioselective oxidation of steroids is possible by such remote photo-induced hydrogen abstractions 82>. 

Allylic oxidation of steroids, particularly at the 7-position, has evoked interest over many years. For example, chromium trioxide-acetic acid," sodium dichromate,and r-butyl chromate have all been used in the oxidation of the 5-a-pregnane series e.g. equation 26). 

Simple ketone substrates served to demonstrate the process. Thus bicyclic ketone (32) was oxidized at -22 C to generate a mixture of diastereomers (33) in good yield. Good stereoselectivity was observed in the oxidation of steroidal ketone (34) to the hydroxy ketone (35). Application of the procedure in syn-... 

Oxidation of steroid S,7-dienes. The main product (about 60% yield) of the oxidation of A -cholesterol (1) or the corresponding acetate with potassium permanganate under neutral or slightly basic conditions is the all-cis-epoxydiol 2. Minor products are the 3j3,5a,6a-trihydroxy-A -steroid and the 3fi,5a,6a,7a-tetrahydroxy-A - and A -steroids, probably formed from 2 by cleavage and dehydration. A precedent for the formation of 2 is the permanganate oxidation of 1,3-cyclohexadiene to an all c/s-epoxydiol in unspecified yield. ... 

Table 9. O,-Oxidation of Steroids and [2,3] Sigmatropic Rearrangement of 5-Hydroperoxysteroids...

Oxidation of steroidal alketies. Mercuric acetate (2 eq.) reacts with A -steroids (I) to give as the major product A -15-ones (2) rather than the expected allylic acetates, 16(J-acetoxy-14-enes. The tetrasubstituted bond of A -cholestene is unreactive under the same conditions. A -Cholestene (disubstituted) reacts only slowly to give A -cholestene-3-one in 20 % yield with 70% recovery of the starting material. This unexpected reaction of steroidal trisubstiluted double bonds may proceed through an allylic acetoxylation followed by an oxidation step. 

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