Asymmetric reactions, of lithium enolate esters

Stoichiometric and catalytic asymmetric reactions of lithium enolate esters with imines have been developed using an external chiral ether ligand that links the components to form a ternary complex.36 The method affords /i-lactams in high enantiomeric excess. 

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. 

Oxaziridines. Davis has developed the use of chiral 2-sulfonyloxaziridines derived from camphorsulfonic acid as chiral auxiliaries in the asymmetric oxidation reactions. Although other oxaziridines may be preferable, the camphor-derived oxaziridines can be used for the oxidation of sulfides and disulfides to sulfoxides and thiosulfinates as well as for the epoxidation of alkenes. On the other hand, the camphoryloxaziridines are the preferred reagents for hydroxylation of lithium enolates of esters, amides, and ketones, as utilized in the synthesis of kjellmanianone (eq 17). ... 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

The reactions of aldehydes with enolates of acetic esters (MeCOOG ) 1.18 (R = H) are often poorly selective [66, 147, 209, 408, 1186, 1258], For this reason, the asymmetric synthesis of acetate aldols is usually performed by reduction of a-bromo analogs with BU3S11H [1254] or from sulfoxides [1049] (see below). However, the reactions of lithium or magnesium enolates of monoacetates of (hols... 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

Asymmetric formation of /i-lactams (38) in high ee has been achieved by reaction of achiral imines (36) with a ternary complex of achiral lithium ester enolate (35), achiral lithium amide, and a chiral ether ligand (37) (in either stoichiometric or catalytic amount) 45 the size and nature of the lithium amide have a considerable effect on the enantioselectivity of the ternary complex. 

Chiral di- and tetraethers were also employed successfully in the aldol reaction. The best results were obtained with imines (vide infra), albeit significant e.e. were also reported reacting the lithium enolates of BHA esters with benzaldehyde609. An example of (—)-sparteine-mediated asymmetric aldolization between a protected glycine lithium enolate and a set of aldehydes was also reported not too long ago (Scheme 131). Medium to good yields and e.e. values were measured610. 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

An approach to lactone [12] similar in concept to that just described, but not requiring a resolution, involved asymmetric Diels-Alder reaction of (benzyloxymethyl)cyclopentadiene [21] with the chiral ester of acrylic add and 8-phenylmenthoI (22), The adduct [22] was obtained in undetermined but apparently quite high e.e. Oxidation of the ester enolate of [22], followed by lithium aluminum hydride reduction, gave diol [23] as an... 

T. Nakata et al. developed a simple and efficient synthetic approach to prepare (+)-methyl-7-benzoylpederate, a key intermediate toward the synthesis of mycalamides. The key steps were the Evans asymmetric aldol reaction, stereoselective Claisen condensation and the Takai-Nozaki olefination. The diastereoselective Claisen condensation took place between a 5-lactone and the lithium enolate of a glycolate ester. 

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