Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination

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.