Unsaturated steroidal ketones

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. 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

With the exception of the parent compounds, where the Michael adducts are isolated, acrylic esters [see, e.g. 6,7,31,105,111 ] and nitriles [6,7], and vinyl ketones [26, 113, 115] generally yield the cyclopropanes (Table 7.6) under the standard Makosza conditions with chloroform. Mesityl oxide produces a trichlorocyclopropy-lpropyne in low yield (10%) [7]. When there is no substituent, other than the electron-withdrawing group at the a-position of the alkene, further reaction occurs with the trichloromethyl anion to produce spiro systems (35-48%) (Scheme 7.12) [7, 31]. Under analogous conditions, similar spiro systems are formed with a,p-unsaturated steroidal ketones [39]. Generally, bromoform produces cyclo adducts with all alkenes. Vinyl sulphones are converted into the dichlorocyclopropane derivatives either directly or via the base-catalysed cyclization of intermediate trichloromethyl deriva-... 

Fluoroxytrifluoromethane, a source of electrophilic fluorine, has recently been employed by Barton et ah for the fluorination of unsaturated steroids.143,144 It is more reactive than perchloryl fluoride and therefore not without danger. It forms, for instance, a highly explosive product with pyridine.143 Like perchloryl fluoride it reacts with enol ethers, esters and enamines, but at lower temperature (— 78°) to yield the fluorinated ketones as well as addition... 

The reaction of unsaturated steroids with nitrosyl fluoride leads to fluoro-substituted nitrimines 1 which arc hydrolyzed to a-fluoro ketones 2. ... 

The base-catalysed methylation of other unsaturated steroid ketones is determined both by their ease of enoHsation and also by the accessibility of the reaction site to the bulky methylating species. Cholest-5-en-7-one reacted in a manner analogous to cholest-4-en 3"0ne, giving the 6,6-dimethyl compound (17) [172], and other unsaturated ketones (A8b >-i5-one A -ii-one [X73], and A i >-7-one [174]) each... 

Hydroxylations of steroidal and unsaturated steroidal ketones in different positions are accomplished by microorganisms, a fact that shows how much ahead microorganisms are in synthetic chemistry as far as regio-... 

Saturated 5/3- and 4 -unsaturated steroid 3-ketones react with hydrogen peroxide in solution in /-butanol containing hydrochloric acid to form bishydroperoxides (5,6) in good yield. "... 

The regio- and stereoselective photobromination of progesterone (464), an a, p-unsaturated steroid ketone, gave the 6( -hrominated product 465 (Scheme 6.223).1305 The reaction was carried out in the presence of cyclohexene oxide to trap HBr formed during the reaction. 

Nitrosyl fluoride reacts slowly (10 days at 3 °C) with 9(ll)-unsaturated steroids to produce 9a-fluoro-ll-nitrimines in 10—70% yield. The nitrimines may be reduced catalytically or with Raney nickel (without affecting 4-en-3-one functions) to 11-imines or by sodium borohydride to nitramines. Both the 11-imines and the 11-nitrimines can be hydrolysed to the corresponding 11-ketones (61— 100% yields), thereby providing another method for the preparation of 9a-fluoro-11-ketones. Further reduction of the 9-fluoro-l 1-imines either catalytic-ally or with sodium borohydride gives 9a-fluoro-11-amino-derivatives, although reduction with sodium and propan-l-ol affords, after acetylation, 1 l( -acetamido-pregnanes with loss of fluorine. 

The reversible nature of the above reaction was demonstrated by Verley5 in 1925 and shortly thereafter by Pondorff,6 but it was not until 1937 that Oppenauer showed that unsaturated steroid alcohols 5 could be oxidized to the corresponding ketones 6 through action of aluminum /-butoxide in the presence of a large amount of acetone in excellent yields.1... 

Unsaturated steroidal ketones represented by the partial structure shown here are... 

Condensation of 2-mercaptoethanol or 3-mercaptopropanoI with ketones is usually achieved with the aid of an acid catalyst. Hydrogen chloride has been used but more common agents are boron trifluoride , freshly fused zinc chloride or p-toluenesulphonic acid . An exchange method between 2,2-dimethyl-1,3-oxathiolane or 2,2-dimethyl-1,3-oxathiane and a non-volatile ketone leads to formation of the new mono-thioacetal and acetone . The equilibrium is displaced by continuous distillation of the acetone formed (equation 71). With saturated ketones, mostly steroids, the yields of the above methods are comparable and are usually in the 60-90% range. With a,j3-unsaturated ketones, the yields were significantly lower . 

Kuball H-G, Neubrech S and Schonhofer A (1992) Optical activity of oriented molecules, a, y5-unsaturated steroid ketones and their sector rules. Chemical Physics 163 115-132. 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

---