Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination

摘要

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 are 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 provide some insight into the basis for selectivity. Examination of the observed products at low conversion suggests that the initial catalytic bromination may be regioselective and stereochemistry-determining. A complex between catalyst and substrate is observed by NMR, revealing a specific association. Finally, products of these reactions may be subjected to regioselective metal-halogen exchange and trapping with I2, setting the stage for utility.