Lithium enolate, protonation

SCHEME 31.1. Marckwald s first enantioselective decarboxylative protonation and Duhamel and Plaquevent s enantioselective lithium enolate protonation. 

A partial explanation of the above findings must lie in the known ease of addition of nucleophilic reagents to the conjugated double bond of pregn-16-en-20-ones. The amide ion that is a by-product of the reduction probably adds to a portion of the unreduced pregn-16-en-20-one giving the lithium enolate of amino ketone (74). This enolate may well be relatively stable at — 33° and would be protonated to the free 16-amino-20-one during work-up... 

Unless a proton donor is added, the lithium-ammonia reduction of an cnone leads to the lithium enolate and lithium amide. The latter is a sufficiently strong base to rapidly convert the mono-alkylated ketone into its enolate, which can be further alkylated. The function of the... 

Other organometallic compounds that are hydrolyzed by water are those of sodium, potassium, lithium, zinc, and so on, the ones high in the electromotive series. Enantioselective protonation of lithium enolates and cyclopropyllithium compounds have been reported. When the metal is less active, stronger acids are required. For example, R2Zn compounds react explosively with water, R2Cd slowly, and R2Hg not at all, though the latter can be cleaved with concentrated HCl. How-... 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

In 1998, Hasanayn and Streitwieser reported the kinetics and isotope effects of the Aldol-Tishchenko reaction . They studied the reaction between lithium enolates of isobu-tyrophenone and two molecule of beuzaldehyde, which results iu the formation of a 1,3-diol monoester after protonation (Figure 28). They analyzed several aspects of this mechanism experimentally. Ab initio molecular orbital calculatious ou models are used to study the equilibrium and transition state structures. The spectroscopic properties of the lithium enolate of p-(phenylsulfonyl) isobutyrophenone (LiSIBP) have allowed kinetic study of the reaction. The computed equilibrium and transition state structures for the compounds in the sequence of reactions in Figure 28 are given along with the computed reaction barriers and energy in Figure 29 and Table 6. 

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... 

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. 

Shibasaki has shown that ALB is also effective for the three-component coupling of enones, aldehydes, and malonates [23]. The above-mentioned mechanistic consideration suggested that the reaction of a lithium enolate derived from a malonate derivative with an enone would lead to the formation of an intermediary aluminum enolate. Thus, further studies were carried out to obtain direct evidence for the formation of an aluminum enolate. The larger electronegativity of aluminum (1.5) as compared with that of lithium, sodium, or lanthanoid suggests that the protonation of the aluminum enolate should be slower than that of the corresponding lithium, sodium, and/or lanthanoid enolates. Then, is it possible to trap such an Al-enolate by an... 

Reviews have featured asymmetric protonations of enol derivatives133 and of enolates and enols.134 Highly enantiofacial protonation of prochiral lithium enolates has been achieved using chiral /J-hydroxy sulfoxides.135... 

Commercially available amino acid derivatives have been tested as chiral proton sources for protonation of lithium enolates catalytic A -L-aspartyl-L-phenylalanine methyl ester gave an ee of 88%.292... 

A stereoselective enolate protonation has been achieved by changing the counterion of the chiral alkoxide base employed the lithium alkoxide-generated enolate gives close to 90% of the /i-cpimcric ketone product, whereas the use of the potassium cation gives 99% a-epimer.293... 

Alkali metal counterion has been found to control the enolate protonation stereoselectivity.12 This remarkable phenomenon has been reported for lithium and potassium enolates of a norborneol derivative. 

Asymmetric protonation of lithium enolates has been examined using commercially available amino acid derivatives as chiral proton sources.139 Among the amino acid... 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

A convenient method for the specific introduction of 2H or 3h (or both) into a molecule is by ketone reduction with labeled metal hydride. Beale and MacMillan (10) have utilized this method for the preparation of GAs labeled at the 1, 2 or 3 positions from GA3 or GA7 (Figure 12). One point of interest is the lithium borohydride reduction of the enone formed by manganese dioxide oxidation of GA3 or GA7. When the reaction is carried out in anhydrous tetrahydrofuran it proceeds in two steps. Initially the lithium enolate is formed which incorporates a proton at carbon-2 from the acid used in the work-up, forming the 3 ketone. This ketone is reduced to the 3 -alcohol by the borohydride which is decomposed more slowly than is the lithium enolate. Thus it is possible to introduce two different labels in a single reaction. 

So when chemists at Dortmund wished to make the syn compound 49, they chose to add diallyl copper lithium to the enone 50 with one side chain already in place." This gave the lithium enolate 51 and protonation gave the syn compound 49. The choice of acid was important phenols were good and 52 was the best. 

Thermodynamic control dominates when a cis ring junction is preferred, as between the flat five-membered and the six-membered ring in 55. Reversible protonation of the lithium enolate 54 occurs on the same face as the methyl group on the exo face (chapter 12). The molecule prefers a folded conformation. 

Reductive O-debenzylation yielded lV-hydroxyazetidin-2-one 373 (Scheme 55) <2000T5719>. The latter compound afforded iV-tosyloxyazetidin-2-one 374 on treatment with TsCl in triethylamine. A substituent with an active methine proton on the ring nitrogen underwent benzylation via a lithium enolate (Equation 148) <1995ACR383>. 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

In contrast, Koga and coworkers found that enantioselective protonation of lithium enolates of 2-substituted-l-tetralones occurred with a catalytic amount of chiral tetraamine 30 in the presence of water as an achiral proton source [34]. This protonation system is noteworthy, since high enantioselectivities are observed notwithstanding the existence of a large excess of water. 

The best base for making lithium enolates is usually LDA, made from diisopropylamine (i-P NH) and BuLi. LDA will deprotonate virtually all ketones and esters that have an acidic proton to form the corresponding lithium enolates rapidly, completely, and irreversibly even at the low temperatures (about -78°C) required for some of these reactive species to survive. 

Their stability at low temperature means that lithium enolates are usually preferred, but sodium and potassium enolates can also be formed by abstraction of a proton by strong bases. The increased separation of the metal cation from the enolate anion with the larger alkali metals leads to more reactive but less stable enolates. Typical very strong Na and K bases include the hydrides (NaH, KH) or amide anions derived from ammonia (NaNH2, KNH2) or... 

The lithium enolates of carboxylic acids can be formed if two equivalents of base are used. Carboxylic acids are very acidic so it is not necessary to use a strong base to remove the first proton but, since the second deprotonation requires a strong base such as LDA, it is often convenient to use two equivalents of LDA to form the dianion. With carboxylic acids, even BuLi can be used on occasion because the intermediate lithium carboxylate is much less electrophilic than an aldehyde or a ketone. 

Lithium enolates are usually made at low temperature in THF with a hindered lithium amide base (often LDA) and are stable under those conditions because of the strong O-Li bond. The formation of the enolate begins with Li-O bond formation before the removal of the proton from the a position by the basic nitrogen atom. 

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... 

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