Pseudoephedrine amide, asymmetric

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

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. ... 

Asymmetric alkylation of fluorinated pseudoephedrine amides has been employed to synthesize a variety of enantiomerically enriched a-fluoro carboxylic acid derivatives. Pseudoephedrine a-... 

The Myers asymmetric alkylation is a reaction between the enolate of a pseudoephedrine amide and an alkyl iodide in the presence of lithium chloride to give... 

Asymmetric Alkylation. 4-Pseudoephedrine ([IS, 2S]-(+)) is a commodity chemical employed in over-the-counter medications with annual worldwide production in excess of 300 metric tons. The enantiomer, /-pseudoephedrine, is also readily available in bulk and is inexpensive. Pseudoephedrine has been shown to be highly effective as a chiral auxiliary in asymmetric alkylation reactions. Treatment of either enantiomer of pseudoephedrine with carboxylic acid chlorides and anhydrides leads to efficient and selective iV-acylation to form the corresponding tertiary amide derivatives (Table 1). Typically, the only by-product in the acylation reactions is a small amount (<5%) of the A,0-diacylated product, which is easily removed by crystallization or flash column chromatography. Because intramolecular 0- -N acyl transfer within pseudoephedrine 3-amino esters occurs rapidly, and because the A-acyl form is strongly favored under neutral or basic conditions, products arising from (mono)acylation on oxygen rather than nitrogen are not observed. 

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary Unexpected Influence of Additives ... 

The series on asymmetric synthesis then concludes with procedures for the preparation of enantiomerically pure products. The asymmetric syntheses of unnatural a-amino acids by the alkylation of pseudoephedrine glycin-amide is nicely exemplified by the preparation of l-ALLYLGLYCINE and N-BOC-i.-ALLYLGLYCINE. One of the advantages of this method is the ready availability of the chiral auxiliary and the mildness of the conditions required for the hydrolysis of the pseudophedrine amide to provide the a-amino acid. Biocatalytic transformations are also gaining importance in asymmetric synthesis as illustrated by the preparation of... 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

Ephedrine and pseudoephedrine auxiliaries are cheap commercially available compounds and readily accessible without any further modification. Procter and coworkers developed a polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase." The resin-bound amide 109 is deprotonated and alkylated with benzyl bromide to provide enantiopure 110. Treating later with different reagents resulted in the enantioselective formation of various alcohols, acids, and amide in 31-55% yield (overall yields), with ee ranging from 78% to 92% (Scheme 7.23). 

The extension of Myers method to pseudoephedrine glycinamide 30 opened an access to an asymmetric synthesis of a-amino acids. For this purpose, the amide 30 (or its enantiomer) was deprotonated with slightly less than 2 equiv. of LDA (or -butyllithium) in the presence of lithium chloride (6 equiv.). Due to the fact that the amino group of the amide 30 is not protected, three sites are accessible for deprotonation the hydroxyl group of the pseudoephedrine moiety, the NH2 group, and the a-carbonyl hydrogen. Indeed, the authors noticed that the kinetic... 

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