Alkylated pseudoephedrine amides

Alkylation products of pseudoephedrine amides are readily transformed in a single operation into highly enantiomerically enriched carboxylic acids, aldehydes, ketones, lactones or primary alcohols. Alkylated pseudoephedrine amides can be hydrolyzed under acidic or basic conditions to form carboxylic acids. Simply heating a pseudoephedrine amide at reflux in a 1 1 mixture of sulfuric acid (9-18 N) and dioxane affords the corresponding carboxylic acid in excellent chemical yield with little or no epimerization (eq 7). Under these conditions, the substrate initially undergoes a rapid N— -0 acyl transfer reaction followed by rate-limiting hydrolysis of the resulting (3-ammonium ester intermediate to form the carboxylic acid. ... 

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. 

Table 2 Diastereoselective alkylation of pseudoephedrine amides with alkyl halides...

A useful mnemonic for deriving the preferred diastereomer formed in the alkylation reaction of pseudoephedrine amide eno-lates with alkyl halides is as follows the alkyl halide enters from the same face as the methyl group of the pseudoephedrine auxiliary when the (putative) ( -enolate is drawn in a planar, extended conformation (eq 1). ... 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

Epoxides can also be used as substrates in pseudoephedrine amide enolate alkylation reactions, but react with opposite di-astereofacial selectivity (suggesting a change in mechanism, proposed to involve delivery of the epoxide electrophile by coordina-... 

Although alkylation reactions of pseudoephedrine amide enolates are successful with a broad range of electrophiles, a few problematic substrates have been identified. Among these are secondary alkyl halides, such as cyclohexyl bromide, and alkyl halides that are both (3-branched and (3-alkoxy substituted. However, there is evidence that the thermal stability of pseudoephedrine amide enolates may be such that extended reaction times at ambient temperature, or even heating, may be tolerated ... 

Table 3 Diastereoselcetive alkylation of pseudoephedrine amides p -branced electrophiles...

Pseudoephedrine amides with a wide variety of a-substituents, including aryl, branched alkyl,i" chloro, fluoro (described in... 

The diastereoselectivity of the reaction is lower than that obtained in benzylations of pseudoephedrine amide enolates lacking the a-hydroxyl group. Although an extensive series of 0-protected derivatives of a-hydroxyacetamide has been examined in a search for an alternative alkylation substrate [TBS, TBDPS, THP, Bn, BOM, Piv, and methy 1( 1 -methoxyethyl)], none has provided satisfactory results nor offered any improvement over pseudoephedrine a-hydroxyacetamide itself. ... 

Hydrolysis reactions of alkylated pseudoephedrine glycina-mides are more rapid than the hydrolysis of pseudoephedrine amides without a-amino groups. It is believed that this reflects... 

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... 

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