Deprotonation metal enolate generation

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

Deprotonation at the a-carbon atom of a parent carbonylic compound by an adequate base (equation 2) is the most general method, though not exclusive, for generation of metal enolates, thus they frequently are presented as activated forms of their carbonylic precursors. 

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. 

Most metal enolates are generated by transmetalation from Li enoiates. However, Ti-enolates can be formed by action of TiCiyz -PrjNEt on carbonyl confounds [404,1042] and Zr-enolates can be generated by similar reactions with Zr(0-/ert-Bu)4 [1245], Lithium E-endates are obtained by deprotonation of ketones or esters with a branched Li-amide (LDA, LICA, LOB A, LTMP) in a weakly polar medium (THF or THF-hexane), while Z-enolates are formed by using LDA or LHMDS in the presence of HMPA or DPMU [1016], Tertiary amides always give Z-endates, and difunctionalized derivatives such as Evans s oxazolidinones 5.30 and 5.31 are chelated to the metal prior to enolization. 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination... 

Another classic in asymmetric synthesis is Oppolzer s sultam 91 [48], and various JV-acyl derivatives 92 were used - inter alia - for diastereoselective alkylations. Early attempts for enolate generation from amides 92 were plagued by competing deprotonation at carbon 10, adjacent to the sulfonyl group, but regioselective metallation at the a-carbonyl position was achieved by treatment with -butyllithium, LICA, or NaHMDS. The method is applicable not only to the sultam derived from propionic acid 92 (R = Me) but also to substituted and... 

An aldol reaction of preformed enolates requires three individual steps the irreversible generation of the metal enolate 143 (mostly by deprotonation but also by alternative methods outlined in Chapter 2), the addition of the aldehyde that leads to a metal aldolate 144, and, finally, the hydrolysis that yields the fi-hydroxy carbonyl compound (Scheme 4.28). Usually, the first two steps are performed in a one-pot reaction and the third one in the course of a quenching operation at the beginning of the work-up procedure. In the aldolate 144, the metal is generally chelated, a feature that contributes to its thermodynamic stability and... 

Hydridotris(3,5-dimethyl-l-pyrazolyl)borate]molybdenum-(i72-acyl) complexes, such as 1, are deprotonated by butyllithium or potassium hydride to generate enolate species, such as 488.8> jjie overa]] structure of these chiral complexes is similar to that of the iron and rhenium complexes discussed earlier the hydridotris(3,5-dimethyl-l-pyrazolyl)borate ligand is iso valent to the cyclopentadienyl ligand, occupying three metal coordination sites. However, several important differences must be taken into account when a detailed examination of the stereochemical outcome of deprotonation-alkylation processes is undertaken. 

More reactive carbon nucleophiles than enolates can also be prepared on insoluble supports (see Chapter 4) and are used to convert aldehydes or ketones into alcohols. Organolithium compounds have been generated on cross-linked polystyrene by deprotonation of formamidines and by metallation of aryl iodides (Table 7.5). Similarly, support-bound organomagnesium compounds can be prepared by metallation of aryl and vinyl iodides with Grignard reagents. The resulting organometallic compounds react with aldehydes or ketones to yield the expected alcohols (Table 7.5). 

With this end in view, phenyldimcthylsilyl tri-n-butylstannane was added under the influence of zero-valent palladium compound with high regioselectivity and in excellent yield to the acetylene 386 to give the metallated olefin 387 (Scheme 56). The vinyl lithium carbanion 388 generated therefrom, was then converted by reaction with cerium(lll) chloride into an equilibrium mixture (1 1) of the cerium salts 389 and 390 respectively. However, the 1,2-addition of 389 to the caibonyl of 391, which in principle would have eventually led to ( )-pretazettine, did not occur due to steric reasons — instead, only deprotonation of 391 was observed. On the other hand, 390 did function as a suitable nucleophile to provide the olefinic product 392. Exposure of 392 to copper(II) triflate induced its transformation via the nine membered enol (Scheme 55) to the requisite C-silyl hydroindole 393. On treatment with tetrafluoroboric acid diethyl ether complex in dichloromethane, compound 393 suffered... 

In Figure 13.1, the enolate structures are shown with the charge on the heteroatom and with the heteroatom in association with a metal ion. The metal ion stems from the reagent used in the enolate formation. In the majority of the reactions in Chapter 13, the enolate is generated by deprotonation of C,H acids. The commonly employed bases contain the metal ions Li , Na , or K . Therefore, in Chapter 13, we will consider the chemistry of lithium, sodium, and potassium enolates. 

Fig. 13.17. Highly "Z"-selec-tive generation of ester enolates in a THF/DMPU solvent mixture (DMPU, /V,/V -dimethyl-propyleneurea). The transition state A of this deprotonation with a metal-free diisopropy-lamide anion (in solution) corresponds to the calculated transition state B of the deprotonation of propionic aldehyde with a hydroxide anion (in the gas phase).

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