Metal-stabilized enolates

Addition Reactions of Metal Enolates of Non-stabilized Esters, Amides, and Ketones to Epoxides... 

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

The oxidative insertion of zinc into a-halo carbonyl compounds and the subsequent reaction of the zinc enolates formed with various electrophiles can either be carried out in a one-pot Barbier-type fashion or in two consecutive steps.1-3 Zinc enolates exhibit a reasonably high stability over a wide temperature range (from -78°C to above 80°C for short periods of time) compared to other metal enolates. Although it has been reported that solutions of BrZnCH2COOtBu can be stored for several days without loss in activity,5 it is generally advisable to use freshly prepared reagents in order to avoid... 

The addition of an alkaline earth metal enolate A to a carbonyl compound is always an exer-gonic process irrespective of whether the enolate is derived from a ketone, an ester, or an amide and whether the carbonyl compound is an aldehyde or a ketone (Figure 13.44, top). One of the reasons for this exergonicity hes in the fact that the alkaline earth metal ion is part of a chelate in the alkoxide B of the aldol addition product. The driving forces for the additions of alkaline earth metal enolates of esters and amides to carbonyl compounds are further increased because the aldol adducts B are resonance-stabilized, whereas the enolates are not. 

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

Metal enolates of carbonyl compounds are important nucleophiles in C—C bondforming reactions for the synthesis of nonfluorinated compounds. However, the metal enolates of fluorinated carbonyl compounds have been severely limited to a-F metal enolates, which can be stabilized by chelate structures containing the M—F moiety. In sharp... 

Tantalum enolate chemistry shows the dichotomy for the carbonylation reaction " of Cp Ta(CH2R)Cl3 with CO which results in the mono-THF adduct of rj -acyl complex Cp Ta(0=CCH2R)Cl3(THF) for R = t-Bu (the acyl group is anionic) but the isomeric enolate Cp Ta((Z)-7j -OCH=CHR)Cl3 for R = p-Tol. This invites the question of the relative thermodynamic stabilities of metal complexes of RCH2CO and RCHCHO and additionally the question of Z vs. E enolate stabilities. Only for organometalhc compounds (X = [M]) do we find examples where RCH2COX is less stable than RCH=CHOX. 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

A few comments concerning the crystallization of carbanions are in order. These comments are based upon the personal experience developed in our own laboratory and also upon observations noted in the literature in the course of crystallizing enolate anions. Although alkali metal enolate anions are relatively unstable compounds, they have been prepared in the solid state, isolated, and characterized by IR and UV spectroscopy in the 1970s. Thus the ot-lithiated esters of a number of simple esters of isobutyric acid are prepared by metallation of the esters with lithium diisopropylamide in benzene or toluene solution. The soluble lithiated esters are quite stable at room temperature in aliphatic or aromatic hydrocarbon solvents and are crystallized out of solution at low temperature (e.g. -70 °C.). Alternatively the less soluble enolates tend to precipitate out of solution and are isolated by centrifugation and subsequent removal of the solvent. Recrystallization from a suitable solvent can then be attempted. The thermal stability of the lithiated ester enolates is dramatically decreased in the presence of a solvent with a donor atom such as tetrahydrofuran. 

Recent research by Bergbreiter, Newcomb, Meyers and their respective coworkers has shown that a variety of factors, such as the base, the temperature of deprotonation, and the size of the substituent on nitrogen, control the structure of the metallated imine and ultimately the regiochemistry of the alkylation reaction. In contrast to metal enolates, where the more-substituted species is usually the more thermodynamically stable, less-substituted sy/i-metallated ketimines, e.g. (89), are the most thermodynamically stable of the possible isomers of unsymmetrical systems. An explanation for the greater stability of syn imine anions compared with anti imine anions has been presented by Houk, Fraser and coworkers. ... 

Thus, present technology permits conjugate addition of stabilized carbon nucleophiles under formally basic (enolate), neutral (enamine), or acidic (Lewis acid) conditions. In general, the softer enamine and enol ether additions show a greater preference for 1,4- over 1,2-addition than do isosteric metal enolates. 

The stereochemistry of the reactions of chiral carbonyl compounds with nucleophiles has been a topic of considerable theoretical and synthetic interest since the pioneering study by Cram appeared in 1952. The available predictive models focus entirely on the conformational and stereoelectronic demands of the chiral carbonyl substrate, the implicit assumption being that the relative stabilities of the competing transition states are determined only by stereoelectronics and the minimization of nonbonded interactions between the substituents on the chiral center and the nucleophile. These models totally ignore the possibility, however, that the geometric requirements of the nucleophile may also have an effect on reaction diastereoselectivity. Considerable evidence is now available, particularly in the reactions of Type I (Z)-crotylboronates and Z(0)-metal enolates, that the stereochemistry of the nucleophile is indeed an important issue that must be considered when assessing reaction diastereoselectivity. 

From the point of view of catalytic strategy, all three of these facts are probably connected. The product of the reaction is a phenol, rather than an enolate, and metal ion stabilization of the product is apparently not needed. The driving force associated with formation of an aromatic compound is evidently sufficient that decarboxylation can be concerted with hydride transfer. The carbon isotope effect on this reaction is surprisingly small, perhaps because the transition state is quite early (65). The isotope effects also indicate that substrate binding is associated with a conformation change, which may seat the substrate in a reactive conformation in the active site. 

By comparison, decarboxylation is largely a kinetic problem. Enzymes have developed a variety of strategies for stabilizing the anionic intermediate that is produced in the decarboxylation step. Metal ion stabilization of enolates is a common theme, particularly for decarboxylation of /8-keto acids. The most elegant solutions are perhaps the extensive electron delocalizations seen in pyri-doxal phosphate and thiamin pyrophosphate. 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

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