Diastereoselective alkylation, of pseudoephedrine amides

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

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). ... 

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. ... 

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. ... 

Furstner et al. used Myers et al. s pseudoephedrine-based alkylation twice in the preparation of different building blocks that were then further elaborated into amphidi-nolides B4 and G1 (Scheme 7.38). In one instance, t-butyl-(2-iodoethoxy)diphenylsilane was used as the alkylating agent, and in the second, 7 -propenoxide was employed. In the former case, a single diastereomer was generated in excellent yield. The epoxide-based alkylation also proceeded in excellent yield, but the diastereoselectivity was somewhat lower (92.5 7.5). In both cases, the alkylated amide product was transformed into the corresponding alcohol in excellent yield. 

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