Lithium enolates association

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Not surprinsingly, the aldol addition of the lithium enolates derived from these systems proved to be unsatisfactory. However, the derived zirkonium enolates in these and related systems have proven to be exceptional 176). The amides (171) and (172), each of which is readily derived from (S)-proline and (S)-valine respectively, exhibit good stereoselectivity with a range of aldehydes. The optical purity of the P-hydroxy amides (173) was very good (>95% e.e.). However, this method has a limitation which has been associated with the acidic conditions that are required to hydrolize these chiral amides (173) to their derived carboxylic acids (174). While... 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

C-Acylation of the lithium enolates derived from 4-methoxybut-3-en-2-ones is achieved with acid chlorides without any significant O-acylation. A general route to pyranones results which avoids the acidic conditions frequently associated with other synthetic methods (80TL1197). Cyclization of these products, which exist in an enolic form, occurs at room temperature in benzene in the presence of a trace of trifluoroacetic acid (Scheme 135). 

It is known that the chemistry of enolates depends on the nature of the metal. Moreover, the metals are an integral part of the structures of enolates. Lithium enolates are most frequently employed, and in the solid state the lithium cations definitely are associated with the heteroatoms rather than with the carbanionic C atoms. Presumably the same is true in solution. The bonding between the heteroatom and the lithium may be regarded as ionic or polar covalent. However, the heteroatom is not the only bonding partner of the lithium cation irrespective of the nature of the bond between lithium and the heteroatom ... 

The further transformations of the enolate C start with a reductive elimination (additional examples of this type of reaction can be found in Chapter 13), which gives the enolate D. This compound is not a normal lithium enolate because it is associated with one equivalent of CuR. The CuR-containing enolate D remains inert until the aqueous workup. As you can see from Figure 8.35, 50% of the groups R contained in the Gilman cuprate are lost through formation of the stoichiometric by-product CuR. This disadvantage does not occur in the 1,4-additions of Normant and Knochel cuprates. 

This difference was assigned to the lesser ionicity of the OLi bond when compared to the OK one. The solvent is likely to play an important role in the equilibrium as well polar solvents seem to favor the more substituted enolate. In addition, House and Trost highlighted the fact that lithium enolates equilibrate very slowly unless a substantial excess of the free ketone is present in the solution64. Note that ab initio calculations on the naked enolates (no associated cation) of 2-butanone (Scheme 9 with R1 = H and R2 = Me) suggest that the primary and Z(O) secondary isomers are almost isoenergetic,65 while the E O) secondary analog is less stable by more than 4 kcalmol-1. Repeating these calculations for the 3-methyl-2-butanone enolates showed that the primary isomer is more stable by 4.3 kcalmol-1. 

The mixed (heterogeneous) complexes of a lithium amide (LDA or LiTMP) and a ketone lithium enolate (acetone, cyclohexanone or diisopropyl ketone) have been examined by semiempirical methods (MNDO) by Romesberg and Collum48. If the stabilization associated with these mixed complexes was not determined, the solvation (by THF and HMPA) of the mixed cyclic dimers and trimers was calculated to be generally exothermic (but decreasingly with the steric demand of the enolate) and led to disolvated entities. A set of solvated dimers, trimers and tetramers, cyclic or not, has thus been identified... 

As shown below (Section IV), the lithium enolates are remarkable vectors of asymmetry. Indeed, the development of many chiral auxiliaries has been associated (in particular through their ester derivatives) with the enolate chemistry. We conclude this section with the contribution of a group of mathematical chemists who have tried to quantify the desymmetrization induced on enolate orbitals by common chiral auxiliaries219. This unusual viewpoint suggests that when the allylic stereogenic center is in the / position, the (Z) isomer has more chirality content than its (E) counterpart. This paper also concludes that in the enolates derived from Meyers oxazolines, the lithium cation distorts the structure but has little influence on its chirality. 

In this fourth part we outline some aspects of the reaction of lithium enolates with electrophilic reagents and their nucleophilic addition onto saturated carbonyl groups. Two significant problems associated with these reactions are (i) the site (C/O) selectivity due to the ambident character of enolates, and (ii) the facial discrimination which controls the stereochemistry of the overall process. 

Evans and Leahy reported on a method for the rhodium-catalyzed allylic alkylation using copper enolates, generated by transmetalation of the corresponding lithium enolates (equation 19). These enolates are softer and less basic nucleophiles than lithium enolates and therefore problems typically associated with enolate nncleophiles in metal-allyl chemistry can be avoided. A copper(I) enolate, derived from acetophenone derivative 63, was used as nucleophile in a regio- and stereoselective rhodinm-catalyzed alkylation of the in situ activated allylic alcohol 62. Thereby, the synthesized ketone 64, a key intermediate in the total synthesis of (—)-sugiresinol dimethyl ether (65), was produced as the only detectable regioisomer with complete conservation of enantiomeric excess. 

The preferred formation of the kinetically favored (Z)-silylketene acetal with amide bases in THF can be rationalized by a cyclic transition state model (128) that enables a close interaction between Li cation, carbonyl oxygen and base (Scheme 23). The presence of additives such as HMPA or DMPU results in a greater degree of solvation of the lithium cation and a weakened Li -caibonyl oxygen interaction. Accordingly, the association between base and ester is diminished and the 1,3-diaxial strain in transition state (129) is reduced, whereas transition state (128) is still destabilized by A -strain." In the presence of a slight excess of ester in the enolization mixture, a kinetic resolution process accounts for an additional increase in the ratio of the ( )- vj. the (Z)-lithium enolate (Table 3). ° ... 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Another major influence on the C 0 ratios is presumably the degree of aggregation. The reactivity at oxygen should be enhanced by dissociation since the electron density is less tightly associated with the cation. With the lithium enolate of acetophenone, for example, C-alkylation is the major product with methyl iodide but C-alkylation and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C 0 ratio is shifted more to O-alkylation by addition of HMPA or other cation-complexing agents. Thus, with four equivalents of HMPA the C 0 ratio for methyi iodide drops from more than 200 1 to 10 1, whereas with dimethyl sulfate the C 0 ratio changes from 1.2 1 to 0.2 1 when HMPA is added. ... 

It is postulated that, in the case of phenylacetates, the degree of aggregation of the lithium enolate is responsible of the poor diastereoselectivities. NMR studies revealed that methyl phenylacetate enolate generated with the Bu-P4 phosphazene base was naked or tightly associated with the Bu-P4H+ cation depending on very small variations in solvent composition. Both forms reacted more rapidly than the corresponding lithium enolate in a model alkylation experiment using dimethyl sulfate. 

Despite some favorable results discussed above, various limitations associated with the use of lithium enolates, such as diaUylation (Scheme 1) and frequently encountered low yields, have also been observed. It is reasonable to state that the Pd-catalyzed allylation of lithinm enolates is at best of rather limited scope, unpredictable, and often disappointing. 

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