Enol ethers steroids

Another preparative method for the enone 554 is the reaction of the enol acetate 553 with allyl methyl carbonate using a bimetallic catalyst of Pd and Tin methoxide[354,358]. The enone formation is competitive with the allylation reaction (see Section 2.4.1). MeCN as a solvent and a low Pd to ligand ratio favor enone formation. Two regioisomeric steroidal dienones, 558 and 559, are prepared regioselectively from the respective dienol acetates 556 and 557 formed from the steroidal a, /3-unsaturated ketone 555. Enone formation from both silyl enol ethers and enol acetates proceeds via 7r-allylpalladium enolates as common intermediates. 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

The general reaction procedure and apparatus used are exactly as described in Procedure 2. Ammonia (465 ml) is distilled into a 2-liter reaction flask and to this is added 165mlofisopropylalcoholandasolutionof30g(0.195 mole) of 17/ -estradiol 3-methyl ether (mp 118.5-120°) in 180 ml of tetrahydrofuran. The steroid is only partially soluble in the mixture. A 5 g portion of sodium (26 g, 1.13 g-atoms total) is added to the stirred mixture and the solid dissolves in the light blue solution within several min. As additional metal is added, the mixture becomes dark blue and a solid (matted needles) separates. Stirring is inefficient for a few minutes until the mass of crystals breaks down. All of the sodium is consumed after 1 hr and 120 ml of methanol is then added to the mixture with care. The product is isolated as in Procedure 4h 2. After being air-dried, the solid weighs 32.5 g (ca. 100% for a monohydrate). A sample of the material is dried for analysis and analyzed as described in Procedure 2 enol ether, 91% unreduced aromatics, 0.3%. The crude product may be crystallized from acetone-water or preferably from hexane. 

A -dien-3-ol ethers gives rise to 6-substituted A" -3-ketones. 6-Hydroxy-A" -3-ketones can be obtained also by autooxidation.Structural changes in the steroid molecule may strongly affect the stability of 3-alkyl-A -ethers. Thus 11 j5-hydroxyl and 9a-fluorine substituents greatly increase the lability of the enol ether/ while halogens at C-6 stabilize this system to autooxidation and acid hydrolysis. 

The photochemical addition of trifiuoroiodomethane to unsaturated systems has been thoroughly investigated by Haszeldine. Little use has been made of this reaction in the steroid field. Irradiation of the enol ether (64) in trifiuoroiodomethane containing pyridine in a quartz vessel furnishes in 60 %... 

The enamines, enol ethers and enol acetates of A -3-keto steroids provide important substrates for fluorination with FCIO3. Reaction of such A -enol ethers and acetates (6) with perchloryl fluoride results in 6a- and 6jff-fluoro-A -3-ketones (7) and (8), the latter representing the more abundant isomer. Tetrahydrofuran or dioxane-water mixtures appear to be particu-... 

It is possible to change the stereochemical result of the alkylation by replacing the 3-ketal protecting group with a A -enol ether. This structural change eliminates a severe 1,3-diaxial interaction to a-face methylation and results in the formation of the 5a-methyl steroid (15) in about 35% yield, ... 

Steroidal 17-cyanohydrins are relatively stable towards chromium trioxide in acetic acid (thus permitting oxidation of a 3-hydroxyl group ) and towards ethyl orthoformate in ethanolic hydrogen chloride (thus permitting enol ether formation of a 3-keto-A system ). Sodium and K-propanol reduction produces the 17j -hydroxy steroid, presumably by formation of the 17-ketone prior to reduction. ... 

Reactions of fluoroxytrifluoromethane with enol ethers, enol acetates, and enamines [/, 2, 3] are very useful, especially for the preparation of steroidal ct-fluoTo ketones (Table 2, entries 1, 3, 5, 6, and 7) [7] (equation 12)... 

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

In view of our results obtained in reactions of the tetrahalogeno-benzynes with aromatic compounds we carried out a reaction of tetra-fluorobenzyne with the A-ring aromatic steroid 3,l7,fl-dimethoxy-oestra-l(10),2,4-triene (119) 154>. As we expected the initially formed enol-ethers were very rapidly hydrolysed and the adducts were isolated as the ketones (120) and (121). The mass spectra of the compounds (120) and (121) did not show molecular ion peaks and as anticipated the ketones were rapidly converted into the naphthalenes (122) and (123) photo-chemically. 

While fluoroxy compounds react well with enol derivatives, fluorine in general does not. However, there are various reports where such reactions are described and in certain cases even with decent yields. In 1982 it was reported that pyruvates with a dominant enolic form react well with fluorine, to give the corresponding fluoro derivatives l.78 Several silyl enol ethers 2 and 379 including ones made from 1,3-dicarbonyl derivatives 480 react quite satisfactorily with fluorine to give the expected a-fluoro ketones. Steroidal 16-enol acetates react with fluorine to form mainly 16a-fluoro-17-oxo steroids e.g. 5.81... 

Enol ethers can be regiospecifically fluorinated to form a-fluoro carbonyl compounds. In this way it is possible to synthesize fluorinated oxo steroids as the carbonyl groups not activated by the trimethylsilyl (or acetyl) enol ethers are not fluorinated.54... 

Fluoropyridinium triflate (la) exhibits high selectivity in fluorinations. In a steroid 8 with two reaction sites, a conjugated and a nonconjugated vinyl acetate moiety, 1-fluoropyridinium triflate (la) reacts at the conjugated site only. On the other hand, steroid 9 with a silyl enol ether and a conjugated acetate moiety affords the product resulting from reaction at the former site only.44,52... 

It was found that the counteranion of the 1-fluoropyridinium salts considerably affects selective fluorinations.54 For example, fluorination with 1-fluoropyridinium triflate (la) was compared to that with l-fluoro-4-methylpyridinium-2-sulfonate (2b) using a steroid 10 containing an acetoxy function and a conjugated trimethylsilyl enol ether as the substrate.54... 

Conjugated enol ether 18 derived from the corresponding a,/J-unsaturated oxo steroid, gives a 1 1 mixture of 6-fluoro-17/ -hydroxyandrost-4-en-3-one (mixture of 6a- and 6/J-isomers) and 4-fluoro-17/J-hydroxyandrost-5-en-3-one upon treatment with 1-fluoropyridinium triflate (la).52... 

Treatment of the silyl enol ether 23 with 1-fluoropyridinium triflate (la) gives the 14a- and 14/i-fluoro steroid C/D-ring ketones.61,62... 

F-Teda BF4 (6) is very effective for the fluorination of a wide variety of organic substrates steroidal enol acetates (Table 7)92 and silyl enol ethers, certain carbanions, mildly activated aromatic compounds, and sulfides bearing oc-H atoms.73,75,76,77,84,88 90 The products are obtained with good yields and regioselectivity under very mild reaction conditions (Table 8). 

---