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Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination

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journal contribution
posted on 27.02.2013, 00:00 by Kimberly T. Barrett, Scott J. Miller
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.