Thermodynamic silyl enol ethers, formation

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

Accordingly, trimethylsilyl enol ethers are enolate precursors (Figure 10.16). Fortunately, they can be prepared in many ways. For instance, silyl enol ethers are produced in the silylation of ammonium enolates. Such ammonium enolates can be generated at higher temperature by partial deprotonation of ketones with triethylamine (Figure 10.18). The incompleteness of this reaction makes this deprotonation reversible. Therefore, the regioselectivity of such deprotonations is subject to thermodynamic control and assures the preferential formation of the more stable enolate. Consequently, upon... 

In our initial investigations,4,22 syn and anti 2-butyry 1-2-alkyl-1,3-dithiane 1-oxides were prepared by our standard means and were enolized using a suitable nonnucleophilic base (LHMDS) in THF at low temperature. The resulting enolate was subjected to alkylation with iodomethane, and the diastereoselectivities were determined by H NMR analysis of the crude product mixture. Our results are summarized in Scheme 5 and Table 4. Interestingly, the enolates were trapped as the corresponding silyl enol ethers, and NMR analysis revealed exclusive formation of one geometrical isomer, presumed to be the thermodynamically more favorable Z isomer.23... 

Since the formation of silyl enol ethers from the corresponding ketones is subject to dther thermodynamic or kinetic control, Ais reagent can be used (as demonstrated in equation 36) to achieve useful regiospecific cleavages. 

Regioselective formation of thermodynamic enolates (or their corresponding silyl enol ethers) can be accomplished by treatment of unsymmetrical ketones with KH, or with KH, t-BuMe2SiCl in the presence of HMPAA ... 

There is no such perfect method for getting enolisation to go on the more substituted side. The best is thermodynamic control in the formation of the silyl enol ether,1011 which gives an approximate 90 10 ratio of 22 25 from 23. Silyl enol ethers can be converted into lithium enolates with MeLi (the by-product is Me4Si useful for NMRs) and hence we can achieve alkylation on the more substituted side, e.g. 26 is benzylated with PhCH2Br to give 27 R = CH2Ph in up to 84% yield.12... 

The aldol reaction is often used to make enones by dehydration of the aldol itself, a reaction which often occurs under equilibrating aldol conditions, but has to be induced in a separate step when lithium enolates or silyl enol ethers are used. In general one has to accept whatever enone geometry results from the dehydration, and this is usually controlled by thermodynamics, particularly if enone formation is reversible. Simple enones such as 46 normally form as the E isomer but the Z isomer is difficult to prepare. When the double bond is exo to a ring, e.g. 47, the E isomer is again favoured, but other trisubstituted double bonds have less certain configurations. 

If the electrophile is a vinyl triflate, it is essential to add LiCl to the reaction so that the chloride may displace triflate from the palladium o-complex. Transmetallation takes place with chloride on palladium but not with triflate. This famous example illustrates the similar regioselectivity of enol triflate formation from ketones to that of silyl enol ether formation discussed in chapter 3. Kinetic conditions give the less 198 and thermodynamic conditions the more highly substituted 195 triflate. 

This approach can use the inherent regioselectivity of silyl enol ether formation (chapter 3) using kinetic or thermodynamic enolisation. Hence kinetic enolisation of enones (chapter 11) occurs on the a side leading to 2-Me3SiO-butadienes such as 222. Epoxidation of this silyl enol ether gives the unstable silyloxy ketone 223 which can be desilylated by fluoride ion and hence transformed into the hydroxyketone 225 or acetoxy ketone 224. These transformations are useful because the hydroxy ketones can be unstable34 (see below). 

A cleavage of the fe/7-butyldiphenylsilyl ether followed by thermodynamic silyl enol ether formation provided (269), which upon exposure to A-iodosuccinimide in tetrahydrofuran and subsequent treatment with tetra-n-butyl ammoniu m fluoride afforded (270). 

Formation of Silyl Enol Ethers. TMS-I in combination with Triethylamine is a reactive silylating reagent for the formation of silyl enol ethers from ketones (eq 22). TMS-I with Hexam-ethyldisilazane has also been used as an effective silylation agent, affording the thermodynamic silyl enol ethers. For example, 2-methylcyclohexanone gives a 90 10 mixture in favor of the tetra-substituted enol ether product. The reaction of TMS-I with... 

Deprotonation at the more substituted alpha carbon is slower since it is more crowded, but the resulting thermodynamic enolate is more stable since it has a more substituted double bond. The thermodynamic enolate is favored when the reaction is allowed to equilibrate using higher temperatures and either an excess of ketone or a weaker base allows the reverse reaction to occur. In another approach, an enolate is trapped with trimethyMyl chloride (TMSCl) to give the thermodynamic silyl enol ether. The reversible mechanism of the silyl enol ether formation, along with the warmer reaction conditions, promotes equilibration, and, therefore, favors the more stable product. 

Formation of Enol Ethers. Bromotrimethylsilane with tri-ethylamine in DMF is an effective medium for production of thermodynamic (Z) silyl enol ethers (eq 11). 

Under the conditions used for the generation of silyl enol ethers of symmetrical ketones, unsymmetrical ketones give mixtures of structurally isomeric enol ethers, with the predominant product being the more substituted enol ether (eq 20). Highly hindered bases, such as lithium diisopropylamide (LDA), favor formation of the kinetic, less substituted silyl enol ether, whereas bro-momagnesium diisopropylamide (BMDA) generates the more substituted, thermodynamic silyl enol ether. A comhination of TMSCl/sodium iodide has also been used to form silyl enol ethers of simple aldehydes and ketones as well as from a,p-unsaturated aldehydes and ketones. Additionally, treatment of a-halo ketones with zinc, TMSCl, and TMEDA in ether provides... 

The combination of trimethylsilyldiethylamine and methyl iodide transforms both the cyclic and the acyclic ketones into silyl enol ethers in high yield, with favored formation of the more thermodynamically stable isomer. 

Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O Mahony utilized a silyl ether temporary eonnection to direct a hydro-hydroxymethylation of enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolac-tone 141. Exposure of 139 to Bu3SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to whieh the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). 

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