Silyl enols ether protonation

Silicon Enolates Silyl enol ethers are well known as stable and easily handled enolates. Several research groups took advantage of this higher stability to develop new and innovative enantioselective protonation protocols (Scheme 31.16). ° However, despite the impressive advances made in the development of enantioselective silyl enol ether protonation the last 20 years, then-use as a synthetically useful tool remains sporadic. Indeed, to the best of our knowledge, there has only been a sole report that was applied to the enantioselective silyl enol ether protonation as a key step for natural product synthesis.i° ° i""... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Enantioselective protonation of silyl enol ethers using a SnCl4-BINOL system has been developed (Scheme 83). 45 This Lewis-acid-assisted chiral Bronsted acid (LBA) is a highly effective chiral proton donor. In further studies, combined use of a catalytic amount of SnCl4, a BINOL derivative, and a stoichiometric amount of an achiral proton source is found to be effective for the reaction.346 347... 

BINOL derivative SnCl4 complexes are useful not only as artificial cyclases but also as enantioselective protonation reagents for silyl enol ethers. " However, their exact structures have not been determined. SnCl4-free BINOL derivatives are... 

Monoalkyl ethers of (R,R) 1,2-bis[3,5-bis(trifluoromethyl)phenyl]ethanediol, 24, have been examined for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals in the presence of SnCU (Scheme 12.21) [25]. The corresponding ketones and carboxylic acids have been isolated in quantitative yield. High enantioselectivities have been observed for the protonation of trimethylsilyl enol ethers derived from aromatic ketones and ketene bis(trimethylsilyl)acetals derived from 2-arylalkanoic acids. 

Scheme 70 Enantioselective protonation of silyl enol ethers...

Cycloheptanones attained better enantioselectivity values than their six-membered analogs and the use of alkyl-substituted silyl enol ethers resulted in only moderate enantioselectivities. Indeed, replacement of P=0 by P=S or P=Se in the phospho-ramide catalyst led to improved results in terms of reactivity as well as enantioselectivity. The catalyst loading could be decreased to 0.05 mol% without a deleterious effect on the enantioselectivity (one example). Optimization experiments revealed the critical influence of the achiral proton source on the reactivity and enantioselectivity. This observation suggests a two-step mechanism for the protonation reaction (Scheme 71). 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

Thereafter, Yamamoto reported the first metal-free Bronsted add catalyzed asymmetric protonahon reachons of silyl enol ethers using chiral Bronsted acid 13c in the presence of achiral Bronsted add media (Scheme 5.34) [61]. Importantly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivihes and enanhoselectivihes for the protonation reaction. 

This rule has been used for the assignment of some diastereomeric silyl enol ethers, e g., 3-trimethylsilyloxy-2-pentene269, where the chemical shifts of the vinyl protons were so similar that a confident differentiation was not possible. 

The abstraction of a proton a to a carbonyl group is not the only method for generating enolates and these alternative methods also offer possibilities for regio- and stereoselectivity. Thus, cleavage of silyl enol ethers (e.g., 1 and 3)9, 12 17 and enol acetates (e.g., 5)18 has been used for the generation of specific enolates. The conditions for these cleavages have to be chosen so that there is no equilibration of the lithium enolates formed. 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

Notes An extremely common and widely used base. Often used to remove an acidic proton leading to a kinetic enolate . When carried out with TMS-C1, the process allows for the isolation of a kinetic silyl enol ether. 

The fir st examples of the highly enantioselective protonation of silyl enol ethers, such as (32), have been reported (68-94% ee), using a complex of SnCLt and the monomethyl ether of BINOL (i )-(33). hr this catalytic cycle, the active catalyst is reprotonated by a bulky phenol (Scheme 10).43... 

Silyl enol ethers of decalones have been synthesized which allow stereoselective protonation of the corresponding enol to be initiated and followed kinetically.291 Pendant groups have been placed so that the relative rates of intermolecular protonation and intramolecular protonation (by the proximate group) can be measured. Examples of groups which give one or other mechanism are detailed CO2- and CO2H typify the latter. 

These chelates are more reactive than non-chelated chlorosilanes in forming a silyl enol ether from ketones. Moreover, careful hydrolysis of a pentacoordinated chlorosilane was shown to give a pentacoordinate protonated silanol that resembles the intermediate in the aqueous hydrolysis of silanes.271... 

The enolate I (Figure 10.46, part 2) behaves inertly until aqueous workup is performed and it is protonated to furnish the saturated ketone J. However, I can also be lurther functionalized with other electrophiles if these are highly reactive. Thus, with methyl iodide or allyl bromide, CuR-containing enolates I often form the alkylation products K (example Figure 13.30). With Me3SiCl they reliably give the silyl enol ethers L (example Figure 13.19). 

For both types of substituent, the effects are more marked on the more distant ((3) proton. If these shifts reflect the true electron distribution, we can deduce that nucleophiles will attack the electron-deficient site in the nitroalkene, while electrophiles will be attacked by the electron-rich sites in silyl enol ethers and enamines. These are all important reagents and do indeed react as we predict, as you will see in later chapters. Look at the difference—there are nearly 3 p.p.m. between the nitro compound and the enamine ... 

Silyl enol ethers hydrolyse by a slightly different mechanism, though the first step is the same— protonation at carbon using the lone pair on oxygen. We have already seen how easy it is to attack silicon with nucleophiles, especially those with oxygen or a halogen as the nucleophilic atom. This tips the balance towards attack by water at silicon for the next step. 

You should look upon silyl enol ethers as rather reactive alkenes that combine with things like protons or bromine (Chapter 21) but do not react with aldehydes and ketones without catalysis they are much less reactive than lithium enolates. As with alkylation (p. 674), a Lewis acid catalyst is needed to get the aldol reaction to work, and a Ti(IV) compound such as TiCl4 is the most popular. 

You might think that the presence of the acidic proton in a carboxylic acid would present an insuperable barrier to the formation and use of any enol derivatives. In fact, this is not a problem with either the lithium enolates or the silyl enol ethers. Addition of BuLi or LDA to a carboxylic acid... 

The redrawn product is a silyl enol ether (Chapter 21) at one end and an oxonium ion at the other. Simple proton removal and hydrolysis of the silyl enol ether in the work-up reveals a furan that can be isolated in 81% yield as the true product. 

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