Protonation of lithium enolates

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-... 

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... 

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

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 alternative method shown in equation 18, using a chiral alcohol, like (S,S)-97, as the chiral Brpnsted acid, affords a high level of facial selectivity for the enantioselective protonation of lithium enolate 95 to give the required 2-methyltetralone (5)-93 in yields and enantiomeric purity similar to those of equation 17 °. The concept of internal versus external proton delivery has been probed ° . The use of disulfonamide (R,R)-9S as chiral Brpnsted acid leads to the (R)-93 enantiomer (equation 19), whereas using as chiral scaffold (R,R)-99, the (V,(V -dilithio salt of (R,R)-99 and acetic acid (as external proton source) gives (S)-93 (equation however, in poorer yield and enantiomeric... 

The protonation of lithium enolates of Schiff bases of racemic a-amino esters leads, after the workup, to a-amino acids of (. configuration with ee as high as 70% (eq 2)7 ... 

A chiral (3, (3, (3 -trifluoro-2 -propanol (14) was used for asymmetric protonation of lithium enolate (15) (Scheme 4.8) [43]. The determining factor for the product chirality in this reaction was found to be the chirality of carbinol carbon, but another chirality of the sulfinyl sulfur also affects the enantiomeric excess of the product. Thus, a binary chelation of the chiral fluorinated alcohol to the lithium was suggested. 

Yanagisawa A, Inanami H, Yamamoto H. Chiral aminobor-ane as a chiral proton source for asymmetric protonation of lithium enolates derived from 2-arylcycloalkanones. Chem. Commun. 1998 1573 1574. 

Yanagisawa A, Kikuchi T, Watanabe T, Yamamoto H. Enantioselective protonation of lithium enolates with chiral imides possessing a chiral amide. Bull Chem. Soc Jpn. 1999 72 2337 2343. 

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. " °... 

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... 

Our research group developed catalytic enantioselective protonations of preformed enolates of simple ketones with (S,S)-imide 23 or chiral imides 25 and 26 based on a similar concept [29]. For catalytic protonation of a lithium eno-late of 2-methylcyclohexanone, chiral imide 26, which possesses a chiral amide moiety, was superior to (S.S)-imide 23 as a chiral acid and the enolate was pro-tonated with up to 82% ee. 

The second section, immediately following this introduction, tries to provide an account on the theory and the methods known to give (stereocontrolled) access to the enolates. The third section gathers the most important descriptions available about lithium enolates in the gas or solid phase, as well as in solution. These data are classified according to the physicochemical techniques employed. The fourth section of this chapter, dedicated to the reactivity of lithium enolates, has been restricted to three of their main applications, namely the protonation, alkylation/acylation and aldolisation reactions. 

However, except when stabilized by either electron attracting or sterically demanding groups, the net result of the protonation of an enolate is the formation of the thermodynamically stable parent carbonyl. For example, on treatment of the lithium enolate... 

SCHEME 74. Kinetic protonation of extended enolate formed by intramolecular addition of lithium... 

Actually, most asymmetric protonations concern lithium enolates, although increased e.e. values have been reported when swapping from Li to Mg or Zn enolates. It would therefore be far beyond the scope of this section to list the numerous examples already described in the literature. Furthermore, an excellent review was published at the end of... 

Nonalkylated 3,4-dehydroprolines 914 were obtained in 76-81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the A -BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88-90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at —30°C). The diastereoselectivity of the reaction was detected by HPLC. 

In the lithium and cesium enolates of o-methoxyacetophenone, the methoxy oxygen coordinates with the smaller lithium cation but not with the cesium cation . Other examples of lithium enolate chemistry include a thermochemical analysis of the aldol reaction of lithiopinacolonate with pivalaldehyde and a comparison of the proton affinities and aggregation states of lithium alkoxides, phenolates, enolates, -dicarbonyl enolates, carboxylates and amidates. Although the lithium enolate of cyclopropanone itself remains unknown, derivatives (accompanied by their aUenoxide isomer) have been implicated in the reaction of a-(trimethylsilyl) vinyl lithium with CO. That both species are seemingly formed is surprising because cyclopropanone enolate is expected to be much less stable than its acyclic isomer cyclopropene is less stable than allene by almost 90 kJmol-. ... 

The imide 6 is an excellent proton source for returning lithium enolates to chiral ketones in ether. The ee value is also greatly influenced by an additive, and LiBr appears to have the best effect. Deracemization of amides by protonation of their enolates in the presence of a chiral l-aryl-l,2,3,4-tetrahydroisoquinoline (catalytic amount) and that of the potassium enolates of A-(2-hydroxypinan-3-ylidene)-a-amino esters have remarkable efficiencies. 

Catalytic enantioselective protonations of metal enolates already published can be roughly classified into two methods carried out under basic conditions and acidic conditions. The process under basic conditions is, for example, the protonation of reactive metal enolates such as lithium enolates with a catalytic amount of chiral acid and an excess of achiral acid. The process under acidic conditions employs silyl enol ethers or ketene silyl acetals as substrates. Under the influence... 

The first example of catalytic enantioselective protonation of metal enolates was achieved by Fehr and coworkers (Scheme 3) [44]. They found the enantioselective addition of a lithium thiolate to ketene 41 in the presence of an equimolar amount of (-)-iV-isopropylephedrine (23) with up to 97% ee. Based on the results, they attempted the catalytic version for example, slow addition of p-chlo-rothiophenol to a mixture of ketene 41 (1 equiv) and lithium alkoxide of (-)-N-isopropylephedrine 23-Li (0.05 equiv) gave thiol ester 43 with 90% ee. First, the thiol is deprotonated by 23-Li to generate lithium p-chlorothiophenoxide and 23. The thiophenoxide adds to the ketene 41 leading to Z-thiol ester enolate which is presumed to react with the chiral amino alcohol 23 via a four-membered cyclic transition state 42 to form the product 43 and 23-Li. The hthium alkoxide 23-Li is reused in the catalytic cycle. The key to success in the catalytic process is that the rate of introduction of thiophenol to a mixture of the ketene 41 and 23-Li is kept low, avoiding the reaction of the thiol with the intermediate hthium enolate. 

Scheme 3.24. Intrasupramolecular enantioselective protonation of an enolate. The lithium amides are illustrated as monomers for simplicity the aggregation states are unknown, (a) [30,122]. (b) [32,132].

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