Stereoselectivity metal enolate formation

Magnesium enolates are similar to alkali metal enolates. For example, often the same stereoselectivity is observed in their formation and in the aldol reactions of these enolates. 

Stereoselective aldol reactions are limited by their ability to obtain stereoisomerically pure ( )- or (Z)-enolates separately, and it has been suggested that equilibration may be occurring to erode the enolate selectivities. However, it would appear that the measured rate of enolate equilibration appears to be too low to be much of an influence.It was suggested by Ireland in 1976 that LDA-mediated enolizations may proceed by cycUc transition states via disolvated LDA monomers. Tbis mecbanism bas since been widely cited for its predictive power. Ireland proposed that the deprotonation process may be proceeding via one of two proposed transition states, where proton transfer is synchronous with metal ion transfer. Non-bonded interactions between amide alkyl groups and the enolate alkyl group cause a preference for E-enolate formation (Scheme 1, refs 124,136). 

Sterically Hindered Base for Enolate Formation. Like other metal dialkylamide bases, sodium bis(trimethylsilyl)amide is sufficiently basic to deprotonate carbonyl-activated carbon acids and is sterically hindered, allowing good initial kinetic vs. thermodynamic deprotonation ratios. The presence of the sodium counterion also allows for subsequent equilibration to the thermodynamically more stable enolate. More recently, this base has been used in the stereoselective generation of enolates for subsequent alkylation or oxidation in asymmetric syntheses. As shown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate alkylation with lodomethane proceeded with excellent diastereoselectivity. In this case, use of the sodium enolate was preferred as it was more reactive than the corresponding lithium enolate at lower temperatures. 

Carbon-carbon bond formation by using metal enolates as synthons in organic chemistry and the protonation, alkylation, arylation, and vinylation of enolates have been reviewed. " The stereoselective carbon-carbon formation of bond through Mannich reaction has been detailed according to the type of Mannich base produced. Phosphine-catalysed asymmetric additions of malonate esters to y-substituted allenoates and aUenamides have been reported. ... 

Note There is an exceptional formation of C-C bonds in derivatives of vicinal diols. An interesting stereoselective method for the synthesis of anfi-vicinal diols uses organometallic alkoxyallyl tins (y-metallated enol-ethers) and aldehydes in the presence of BF3 Et20 at -78 °C [8]. The reagents and reaction conditions limit this method to the laboratory scale. 

It is also possible to introduce additional functionality into the cK-silyl ester. Thus f-butyl (trimethylsilyl)chloroacetate reacts with carbonyl compounds after ester enolate formation with LDA to form f-butyl Q -chloro-a, 8-unsaturated esters, although the elimination of the silyl moiety may have to be encouraged by the use of thionyl chloride, as it also is with the a-bromo analog. A second silyl group, with its additional bulk, can allow for high stereoselection, although the outcome does depend on the metal counterion used in the enolate. ... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

Metal enolates play an important role in organic synthesis and metal enolate-mediated aldol type reactions, in particular, are very useful synthetic tools in stereoselective and asymmetric carbon-carbon bond formation. Generation and reactions of different metal enolates have been extensively studied and successful applications to the controlled formation of carbon-carbon bonds have been realized under mild conditions. 

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... 

The deprotonation of carbonyl compounds 1 (Equation 2.1) leads to diastere-omeric cis- and/or trans-enolates unless precursors with two identical residues R have been chosen. As the configuration at the enolate double bond has a crucial effect on the stereochemical outcome of almost all the consecutive reactions, the controlled preparation of cis- and traws-enolates is prerequisite to any successful application in asymmetric synthesis. It is therefore not surprising that enormous effort was put into the elaboration of protocols for selective formation of the diastereomers of preformed, O-metal bound enolates. This search led to the insight that stereoselective enolate formation depends on a multitude... 

It is widely accepted that Lewis acids play very important roles in aldol reactions first for electrophilic activation of carbonyl group through the coordination complex formation, for the control of regio- and stereoselectivity of the product and for the modification of metal enolates. For these purposes, a variety of combination of metal and ligand has been extensively studied. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

At the first step, the insertion of MMA to the lanthanide-alkyl bond gave the enolate complex. The Michael addition of MMA to the enolate complex via the 8-membered transition state results in stereoselective C-C bond formation, giving a new chelating enolate complex with two MMA units one of them is enolate and the other is coordinated to Sm via its carbonyl group. The successive insertion of MMA afforded a syndiotactic polymer. The activity of the polymerization increased with an increase in the ionic radius of the metal (Sm > Y > Yb > Lu). Furthermore, these complexes become precursors for the block co-polymerization of ethylene with polar monomers such as MMA and lactones [215, 217]. 

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

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