Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination

J Am Chem Soc. 2013 Feb 27;135(8):2963-6. doi: 10.1021/ja400082x. Epub 2013 Feb 14.

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 I(2), setting the stage for utility.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzamides / chemical synthesis*
  • Bromine / chemistry*
  • Catalysis
  • Peptides / chemistry*
  • Stereoisomerism

Substances

  • Benzamides
  • Peptides
  • Bromine