Silyl enol ethers, steroidal

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. 

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... 

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... 

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). 

As an extension of this work, Mattay et al. have used this methodology for the construction of unnatural steroid analogues [41]. The polycyclic framework was build-up via a cascade cyclization of the silyl enol ether 32 using DCA as sensitizer (Sch. 19). The two major products 33 were formed with remarkable high trans, //-stereoselectivity. 

Heathcock has reported an anomalous case of ozonolysis of a silyl enol ether. Usually these substrates undergo facile oxidative cleavage in the same manner as alkoies. However, in this instance the a-silyloxy ketone (61) was obtained in quantitative yield. The inteimediacy of a silyloxy epoxide was suggested. A more recent leport has indicated that a similar process is competitive with the simple cleavage reaction, (63a) versus (63b), in the ozonolysis of the steroidal enol ether (62). 

Trimethylsiloxycyclopropanes, readily available from silyl enol ethers and carbene or carbenoid species, constitute, now, very useful synthetic intermediates . Thus, they undergo acid-, base-inducedor thermal ring-opening into a-methylated aldehydes and ketones in very good yields. The reaction is highly regiospecific in the case of an unsymmetrical ketone, monomethylation can be oriented either to the a- or a -position (equation 58) °°. This sequence has been applied to ethylenic ketones and in the steroid field . ... 

Ketones cannot be directly fluorinated by (difluoroiodo)arenes however, a-fluoroketones can be prepared by the reaction of silyl enol ethers with difluoroiodotoluene in the presence of BF3 OEt2 and the Et3N-HF complex [22], Some steroidal silyl enol ethers can be converted into the respective a-fluoroketones in a moderate yield [23]. 

In addition, a number of steroidal silyl enol ethers and enol esters have been selectively fluorinated by Selectfluor, as shown below ... 

A series of homo-allylic steroidic alcohols were oxidized with N-methyl morpholine N-oxide (NMO) in the presence of tetrapropylammonium perrhutenate (TPAP) (Eq. 70, see Ch. 9, p. 358).The mechanism probably implies the preliminary oxidation of the alcohol. A labile silyl enol ether is preserved under the conditions specified. 

In a straightforward procedure (Fig. 16) trans-fusion of rings C and D can be established. The a,P-unsaturated ketone occupies a key position. It is produced in the usual way [23] by oxidation of the silyl enol ether of the preceding nonconju-gated ketone with Pd(OAc)2 [24] and converted into the p,y-unsaturated ketone by a deprotonation/protonation sequence. Here the synthetic route merges into the Tor-gov pathway [25] catalytic hydrogenation affords a steroid with the correct configuration at C(14), the transformation of which has already been mentioned (Fig. 4). 

Iodotoluene difluoride reacts with steroidal silyl enol ethers to give a-fluoro-ketones. Whilst the reaction is slower than with xenon difluoride, the rea nt may find use since the stereochemical outcomes of the reactions differ, suggesting an electrophilic mechanism for the latter reagent, but a nucleophilic mechanism (via an iodonium intermediate) for the iodo-arene derivative. 

Bunte, J.O., Rinne, S., Schafer, C., Neumann, B., Stammler, H.-G., and Mattay, J., Synthesis and PET oxidative cychzation of silyl enol ethers build-up of steroidal carbocycles. Tetrahedron Lett., 44, 45, 2003. 

The fluorination of 12, easily prepared from the corresponding triketo steroid, with an equimolar amount of 1 (Scheme 2) shows the remarkable ability of 1 to distinguish di-substituted from tri-substituted enol silyl ethers. The 9a-fluoro steroid 13 is produced in 51% yield (78% based on recovered triketo steroid) and the combined yield of the other fluorinated products is only 4.6%.17 it thus is apparent that 1 reacts almost exclusively with the trisubstituted enol ether moiety. The new, selective direct fluorination at the 9a-position holds considerable promise as a means to prepare biologically important 9a-fiuoro steroids.18... 

Generally useful reagent with a high silyl donor ability will not react with amino groups will not cause formation of enol-ether on unprotected ketone groups especially useful for ecdysones, norepinephrine, dopamine, steroids, sugars, sugar phosphates, and ketose isomers... 

As discussed earlier (see also Chapter 6), oxime derivatives are often prepared for polyfunctional compounds containing ketone groups in order to prevent the formation of mixed enol-silyl ethers. An alternative approach is to use a catalyst to enhance the yield of enol-silyl ethers (see also above. Section 4.2.3, for TMS ethers). The use of potassium acetate in toluene as catalyst is reported to produce a quantitative yield of TBDMS ethers and >96% yield of TBDMS-enol ethers of a, -unsaturated keto steroids [326]. An alternative to this approach, set out below, uses sodium formate to catalyse enol-silyl ether formation with fewer by-products being produced [12, 13]. 

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