Addition alkylated pseudoephedrine amides

Addition of alkyllithium reagents to pseudoephedrine amides leads to the formation of enantiomerically enriched ketones (eqs 9 and 10). The protocol developed to transform alkylated pseudoephedrine amides into ketones was optimized to avoid premature breakdown of the tetrahedral intermediate generated following addition of the organolithium species to the amide. ... 

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. ... 

In the last entry of Table I, it is noted that the reduction had to be done with lithium aminoborohydride (LiH3BNH2). Myers further expanded the utility of this reagent with additional examples of the reduction of alkylated pseudoephedrine amides to chiral alcohols of high ee (Table II), and the reduction of iV,iV-disubstituted dodecanecarboxamides and 1-adamantanecarbox-amides to the corresponding alcohols, respectively (Table III) (5). 

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. 

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

A. G. Myers, L. McKinstry, J. Org. Chem. 1996, 61, 2428. Interestingly, attack from opposite r-faces of the pseudoephedrine amide enolates is found for epoxides and alkyl halides. In this context, the lithium alko-xide function of the chiral auxiliary, seems to be the crucial moiety, directing the addition of epoxides and operating as a screen in the case of alkyl halides. 

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