Chelation effects enolate alkylation

It has been demonstrated that excellent diastereoselectivities for enolate alkylation also are obtained when alkyl substituents are positioned at C(4), C(5) or C(6) of benzamide 5. AryE and methoxy substituents at C(5) also are compatible, but a methyl group at C(3) leads to an inversion of the diastereoselectivity of enolate alkylation. The inverted sense of stereoselection is thought to be a result of a disruption of the internal chelation shown in enolate 6 by steric effects of the neighboring methyl substituent. 5... 

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. ... 

More recently Katsuki and coworkers have reported that (Z)-enolates of a-alkyl and a-heterosub-stituted amides such as (134), derived from pyrrolidine derivatives having a C2 axis of symmetry, undergo very diastereoselective alkylations with secondary alkyl and other alkylating agents in good to excellent chemical yields (Scheme 62) As with prolinol ether amide enolates, it appears that the direction of approach of the alkylating agent to the enolate (134) is controlled mainly by steric factors within the chiral auxiliary, i.e. chelation effects seem to be of little importance. 

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. 

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. 

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). 

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. 

Evans and Takacs23 demonstrated a diastereoselective alkylation based on metal ion chelation of a lithium enolate derived from a prolinol-type chiral auxiliary. This method can provide effective syntheses of a-substituted carbox-... 

The counterion of an enolate has a pronounced influence on competing transition states of enolate reactions. The effect is often the result of cation chelation by the carbonyl oxygen atom and one or more additional basic portions of the reactants. For example, alkylation of chiral enolates may lead to more or less diastereomerically pure products and selectivity often depends on the countercation. The importance of the countercation in controlling enolate reaction product distributions requires that the synthetic chemist has at hand stereoselective methods for the preparation of enolate anions with a wide variety of counterions. This chapter is divided into several sections. The 10 following sections describe important current methods for preparing Li, Mg, B, Al, Sn, Ti, Zr, Cu, Zn and other transition metal enolates. 

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