| Stereocontrolled alkylative construction of quaternary carbon centers. | |
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MedLine Citation:
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PMID: 18788739 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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David A Kummer; William J Chain; Marvin R Morales; Olga Quiroga; Andrew G Myers |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2008-09-13 |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 130 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-10-01 Completed Date: 2008-12-22 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 13231-3 Citation Subset: IM |
Affiliation:
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Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alkylation Amides / chemistry Carbon / chemistry* Models, Molecular Molecular Structure Stereoisomerism |
| Grant Support | |
ID/Acronym/Agency:
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GM007598-30/GM/NIGMS NIH HHS; T32 GM007598-30/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amides; 7440-44-0/Carbon |
| Comments/Corrections | |
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