Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination
- 14 February 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 135 (8), 2963-2966
- https://doi.org/10.1021/ja400082x
Abstract
We report the enantioselective synthesis of atropisomeric benzamides employing catalytic electrophilic aromatic substitution reactions involving bromination. The catalyst is a simple tetrapeptide bearing a tertiary amine that may function as a Brønsted base. A series of tri- and dibrominations were accomplished for a range of compounds bearing differential substitution patterns. Tertiary benzamides represent appropriate substrates for the reaction since they exhibit sufficiently high barriers to racemization after ortho functionalization. Mechanism-driven experiments provided some insight into the basis for selectivity. Examination of the observed products at low conversion suggested that the initial catalytic bromination may be regioselective and stereochemistry-determining. A complex between the catalyst and substrate was observed by NMR spectroscopy, revealing a specific association. Finally, the products of these reactions may be subjected to regioselective metal–halogen exchange and trapping with I2, setting the stage for utility.Keywords
This publication has 39 references indexed in Scilit:
- Assessing Atropisomer Axial Chirality in Drug Discovery and DevelopmentJournal of Medicinal Chemistry, 2011
- Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2Nature Chemical Biology, 2011
- Atropisomerism Observed in Indometacin DerivativesOrganic Letters, 2011
- Revealing Atropisomer Axial Chirality in Drug DiscoveryChemMedChem, 2011
- The Challenge of Atropisomerism in Drug DiscoveryAngewandte Chemie, 2009
- Atropisomeric small molecule Bcl-2 ligands: Determination of bioactive conformationBioorganic & Medicinal Chemistry Letters, 2009
- Structural Analysis and Optimization of NK1 Receptor Antagonists through Modulation of Atropisomer Interconversion PropertiesJournal of Medicinal Chemistry, 2003
- Barriers to rotation about the chiral axis of tertiary aromatic amidesTetrahedron, 1998
- Axially Chiral N-Benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK1 Receptor Antagonists: Determination of the Absolute Stereochemical RequirementsJournal of Medicinal Chemistry, 1998
- Liquid Chromatography on Triacetycellulose, 14 Chromatographic Separation of Enantiomers and Barriers to Enantiomerization of Axially Chiral Aromatic CarboxamidesEuropean Journal of Inorganic Chemistry, 1987