Chelation effects ester enolates

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

Asymmetric hydraxylation of lithium enolates of esters and amides.2 Hydroxylation of typical enolates of esters with ( + )- and (-)-l is effected in 75-90% yield and with 55-85% ee. The reaction with amide enolates with ( + )- and ( — )-l results in the opposite configuration to that obtained with ester enolates and with less enantioselectivity. Steric factors appear to predominate over metal chelation. 

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. 

Isatins have served as valuable precursors for the preparation of oxindoles bearing amino functionality at stereodefined C3. In a report from the Emiua group, isatin derived oxime 91 (Scheme 25) was transformed to the urea derivative 92 which underwent a diastereoselective alkylation at C3 to afford the /-menthol adduct 93 (94 6 dr) [59]. Lithium counterions proved to be more effective than potassium ions for achieving diastereocontrol of the enolate alkylation a mechanism has been suggested involving lithium ion chelation between the oxindole enolate of 92, the carbonyl of the urea fimctionality at C3, and the carbonyl of the menthyl ester electrophile. 

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 also occurs in cyclic 3-keto esters, such as derivatives of enolisable keto esters of cyc/ohexanone and cyc/opentanone. Leonard et al. [31] and Bellamy and Beecher [56] have examined a number of such cases. Non-enolisable keto esters of cyc/ohexanone show absorptions near 1735 cm" and 1718 cm" corresponding to the ester and ketonic carbonyl groups. However, compounds such as ethyl-cyc/ohexanone-2-carboxylate show these bands and two others at 1656 cm" and 1618 cm" which must arise from the chelate structure of the enol form. Leonard et al. [31] associate the first of these new bands with the chelated carbonyl absorption and the second with the double-bond absorption. A similar effect is observed... 

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