title: Stereocontrolled alkylative construction of quaternary carbon centers.
abstract: Protocols for the stereodefined formation of alpha,alpha-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of alpha,alpha-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine alpha-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the alpha-C-H bond with alpha-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common pi-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine alpha-phenylbutyramides are found to undergo highly stereoselective but not stereospecific alpha-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephedrine amide, providing alpha,alpha-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the alpha-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kummer
authors.forename: William J
authors.initials: WJ
authors.lastname: Chain
authors.forename: Marvin R
authors.initials: MR
authors.lastname: Morales
authors.forename: Olga
authors.initials: O
authors.lastname: Quiroga
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
mesh_terms: D000478:Alkylation; D000577:Amides / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000577:Amides; D002244:Carbon
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