Chelation effects enolate formation

Thus, the postulated chelated enolates and their alkylation reaction make the intra-annular chirality transformation possible. This method for enolate formation is the focal point of this chapter, as this is by far the most effective approach to alkylation or other asymmetric synthesis involving carbonyl are compounds. 

S,Sj-diastereoisomer was preferentially obtained when KOH was used as base. As an explanation for this stereodichotomic effect, it was proposed that liNR2 induces the formation of a N,0-chelated syn-enolate, and the reaction with KOH leads to an anti-enolate. The procedure also allowed a,a-disubstituted amino acids to be prepared. 

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. ... 

Although accounting for the gross data, this rationale is not completely satisfactory. Subsequent studies [75] showed that addition of HMPA after enolate formation but before electrophile addition also had an effect on the selectivity of the alkylation, leading Helmchen to speculate that the sulfonamide in Scheme 3.15 (or presumably the urethane in Scheme 3.14) may be chelated to the lithium. Another possibility may be that the enolates are aggregated, and the effect of HMPA is to disrupt the aggregation. Additionally, the difference in selectivity between the E(0)- and Z(0)-enolate alkylations (Scheme 3.15) remains unexplained. 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

Chelation effects in general override the usual preferences in the formation of lithium ester enolates, and the (Z)-configured enolates are obtained nearly exclusively. Therefore the stereochemical outcome of the rearrangement should only be controlled by the olefin geometry in the allyl moiety and by the transition state (chair vs. boat). If substituted allyUc esters of glycolic add or related a-hydroxy-acids are subjected to rearrangement, synthetically valuable unsaturated a-hydroxyadds are obtained, albeit the yield and stereoselectivity strongly depends on the substrate and the reaction conditions used. 

Deprotonation of enols of P-diketones, not considered unusual at moderate pH because of their acidity, is faciUtated at lower pH by chelate formation. Chelation can lead to the dissociation of a proton from as weak an acid as an aUphatic amino alcohol in aqueous alkaU. Coordination of the O atom of triethanolamine to Fe(III) is an example of this effect and results in the sequestration of iron in 1 to 18% sodium hydroxide solution (Fig. 7). Even more striking is the loss of a proton from the amino group of a gold chelate of ethylenediamine in aqueous solution (17). 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

This asymmetric synthesis in a reaction with electrophiles is due to the chirality of the amide enolate created by the generation of intramolecular chelate of the enolate and the oxygen atom. An interesting fact is the effect of the group that participates in the chelation on the induced asymmetric centers. Hydroxyl and methoxyl induce formation of opposing asymmetric centers. Neither this fact nor the mechanism of the reaction and the intermediates involved has been discussed and explained. 

An = Th, U, Np, and Pu. In complexing with metal ions, the / -diketones form planar six-member chelate rings with elimination of the enol proton. The simpler / -diketones, such as acetylacetone (HAA), are fairly water soluble, but form complexes that may be soluble in organic solvents. This is especially true for the An ions which form strong complexes with HAA and can be effectively sequestered to the organic phase, making HAA a potentially useful extractant (See Table 27). The four stability constants in Table 27 for tetravalent actinides imply that four HAA ligands coordinate with each metal ion in the formation of the extracted neutral ML4 complexes. ... 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Scheme 33 illustrates the use of two standard persistent auxiliaries. The Evans oxazolidinone 33-1 [83] is highly versatile, i.e., suitable for enolate reactions and double bond additions alike. In the enolate alkylation case [reaction (99)] the high diastereoselectivity depends on the formation of a chelate 33-2 which fixes the reaction site in a defined conformation in which one of the diastereofaces is efficiently shielded. The removal of the auxiliary requires the chemoselective cleavage of the exo cyclic amide bond which is sometimes difficult to achieve. In boron mediated aldoltype additions [Scheme 34, reaction (100)] no chelate can be formed so that the extremeley high diastereoselectivity with which the syn-adduct 34-1 is formed must be due to some other effect, presumably allyl 1,3-strain on the stage of the enol borinate 34-1. 

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