Steroids enones

Lithium-ammonia reductions of most steroidal enones of interest create one or two new asymmetric centers. Such reductions are found to be highly stereoselective and this stereoselectivity constitutes the great utility of the reaction. For conjugated enones of the normal steroid series, the thermodynamically most stable products are formed predominantly and perhaps exclusively. Thus the following configurations are favored 5a, 8/ , 9a, and in certain cases 14a (see page 35). Starr has listed numerous examples illustrating these facts and Smith " and Barton have tabulated similar data. 

Aside from pregn-16-en-20-ones, no other conjugated steroidal enones that are known to undergo facile nucleophilic addition to the carbon-carbon... 

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. 

Photoaddition of acetylene, 349 Photoaddition of allene, 349 Photoaddition of dichloroethylene, 349 Photoaddition of ethylene, 348 Photoaddition of hexafluoroacetone, 345 Photoaddition of maleic anhydride, 348 Photochemical addition of ethylenes and acetylenes to steroidal enones and dienones, 343... 

Head-to-head coupling to produce pinacols is the exclusive pathway when the 0-carbon is badly sterically hindered, as in steroidal enones and dienones135 137, or the dienone 141 138>. 

The stereochemical outcome of the reaction of steroidal enone 39 changed when adsorbed on alumina [43], Photocycloaddition in methanol occurred from the a side (83 17). In contrast, the fi product was favored when the reaction was carried out on alumina. The observed fi selectivity can be accounted for by the preferential adsorption of the sterically less hindered a side of the enone to the gel surface. 

An interaction between a C(4)-C(5) double bond and the axial halogen atoms in the 6-position of steroidal enones 201 was reported (344) that leads to significant downfield shifts of the C(4) signals. This is reminiscent of what happens in the a-haloketone case (330). 

The molecule methyl-5(10)-octalin-l,6-dione (1) was chosen as model compound for the steroidal enones investigated earlier. Oriented single crystals of (1) were studied at low temperature (4 K). First the crystal structure of (1)... 

Scheme 6.20. Diastereoselective cuprate addition to steroidal enone 95 (MOM = methoxymethyl).

This explanation for the two polarographic waves seen in Figure 3.2 suggests that the region of transition between the two waves will be sensitive to buffer concentration and composition. Such effects are seen in the polarography-pH profiles of steroid enones, some of which [88] show behaviour like that of cyclohexenone while others show only a linear variation of half-wave potential over the whole pH range of 2 — 11 [89, 90]. 

Reduction of steroid enones like cholestenone 26, with a rigid ring conformation, leads to head-to-head pinacol dimers because of steric hindrance at the alternative dimerization site, and reaction occurs tlnough the a-face of the radical intermediate [101, 102]. The a-face is opposite to the angular methyl substituent... 

Alkylation of the steroidal enone 36 provides information about the importance of the reaction conditions for the diastereoselectivity82. The notable difference between the observed d.r. s is difficult to rationalize but clearly the solvent conditions have a strong influence on the structure and aggregation of the intermediate dienolate anion71,82. 

Irradiation of cyclopent-2-enones in the presence of allenes affords mixtures of 6- and 7-methylenebicyclo[3.2.0]heptan-2-ones, the latter regioisomers being formed preferentially.4,5 From cyclohex-2-enones and allene, 8-methylenebicyclo[4.2.0]octan-2-ones are formed regiose-lectively.6 In contrast, six-membered a,/i-unsaturated lactones and allene afford mixtures of regioisomers.7 Mechanistic arguments for the stereochemical outcome of allene photocycloadditions to steroidal enones have been discussed.8... 

Figure 29. A schematic illustration of the face preference for addition of olefins to a steroidal enone in solution and on silica surface. In solution the less-hindered a face is preferred. On silica surface the molecule adsorbs from the less-hindered face exposing the more-hindered face for attack by an olefin.

We recently found that prereduced 7.5% Cu on AI2O3, easy to prepare by conventional techniques, can be conveniently used under very mild conditions (60°C, 1 atm of H2) for the selective hydrogenation of steroidic enones. Thus, CU/AI2O3 allows the chemospecific reduction of a,P... 

Contrary to this bicyclic series, the equilibration of the a- and the b-cyano isomers derived from the steroid enones 92 (R=H or CH3) does not occur. It has also been impossible to produce the B-cyano isomer from the hydrocyanation reaction. This result was explained by the fact that in the steroid series, there is a strong steric interaction between the cyano group and the C-ll methylene group of ring C in the boat-like conformation 95 (cf 98). Consequently, addition to the B-face never occurs in these compounds. This was confirmed by the fact that 1a-cyanocholestanone (derived from 92, [KH3) readily incorporates labeled cyanide (13C=N) under the experimental conditions of the hydrocyanation reaction. 

Ketones and aldehydes are converted to alkenes by the hydrogenolysis of their enol triflates with formate. The steroidal enone 524 is converted to the dienol triflate 525 and then to the 1,3-diene 526 by the hydrogenolysis with tributylammonium formate... 

Photochemical [2 + 2]cycloaddition to enones. This reaction has been shown to occur mainly from the less-hindered a-side of steroidal enones.2 Cycloaddition to the cyclopentenone (1) is also stereoselective, but the stereoselectivity and the yields are dependent upon the solvent. The highest yields are generally obtained in an apolar solvent (such as hexane). 

Method A A solution of 0.3 mmol of the steroidal enone 34 and 1.5 mmol of. S. S-diphenylsulFiliminc (35) in 1 mL of benzene is refluxed for 65 h. The solvent is removed under reduced pressure and the residual matter is subjected to preparative TLC (silica gel, Et20/hexane) yield 77%. 

Method B A solution of 0.2 mmol of the steroidal enone (34, 38) and 0.9 mmol of S.S-diphenylsuirilimine (35) in 3.5 mL of toluene is kept in a high pressure bottle at 6 kbar for 6-48 h (for only one example, a temperature of 80 °C was reported). The solvent is removed in vacuo and the residue is acetylated in 1.5 mL of dry acetic anhydride and 3 mL of pyridine at 20 °C for 24 h. The reaction mixture is diluted wilh 20 ml, of water and extracted with 50 mL of CH2C1,. The extract is dried over Na2SO and the solvent removed in vacuo. The residual solid is subjected to preparative TLC (silica gel, Et20/hexane or EtOAc/hcxanc) yield 5-81 %. 

The use of silica gel surfaces to modify photoprocesses continues to be of interest. The present report deals with photoaddition of alkenes to the steroidal enone (44).It is presumed that, in the adsorbed state on silica gel, the steroid will present the normally hindered side, i.e., the g-face is attacked by the alkene and the a-face is adsorbed on to the gel. The photoadditions were compared with those carried out in methanol. Thus with allene the two photoproducts (45) and (46) were obtained in 90 and 10% yields, respectively, at -78 °C in methanol, while on silica gel, both at -78 °C and at ambient temperature, the same two products were obtained in 46 and 53% yield. Similar results were obtained using ethene and cyclopentene. The photocycloaddition of ethyne and propyne to progesterone and testosterone in solution yields the cycloadducts (47) and (48), with a preference for the former mode of addition being observed. These results are in conflict with those of de Mayo and co-workers. ... 

Better stereosdectivities have been noted for conjugate addition reactions to the steroidal enone 95 (Scheme 6.20, Tab. 6.2). Irrespective of the enone geometry, addition of lithium dimethylcuprate provided the anti addition product 96 in hi yid-d and with good diastereoselectivity (Tab. 6.2, entries 1 and 2). Interestin y, addition of chlorotrimethylsilane to the reaction mixture had a dramatic effect. The E isomer of enone 95 still gave the anti addition product 96 with perfect stereoselectivity (entry 3). "With the 2 isomer of the enone, however, the syn addition product 97 was formed in good yield and with hi diastereoselect vity (entry 4)... 

Correct reagent selection allowed reduction of steroidal enone (74) to either diastereoisomeric allylic alcohol, uncontaminated by its isomer. Sodium borohydride/cerium chloride in methanol-THF gave the equatorial alcohol (73), while L-selectride produced the axial isomer (75) via equatorial attack (Scheme 12). Unexpected axial attack on diketone (76) to give equatorial alcohol (77 equation 19) led to the proposition that for hydride additions to decalones two 1,3-diaxial interactions override one peri interaction which in turn takes precedence over a single 1,3-diaxial interaction. ... 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

The properties of the low-lying excited singlet and triplet states of 19 different steroidal enones have been investigated by phosphorescence excitation spectroscopy, at 77 and 4.2 Information was obtained on the ordering of excited... 

---