A Pd(0)-Mediated Indole (Macro)cyclization Reaction

• Published in: Journal of the American Chemical Society Vol. 135; no. 4; pp. 1600 - 1606
• Main Authors: Breazzano, Steven P, Poudel, Yam B, Boger, Dale L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.01.2013; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Cyclization; Indoles - chemical synthesis; Indoles - chemistry; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Molecular Structure; Organometallic Compounds - chemistry; Palladium - chemistry; Physical Sciences; Science & Technology; PHYSICOCHEMICAL PROPERTIES; ALA-D-LAC; CROSS-COUPLING REACTIONS; CHLOROPEPTIN-I; DIELS-ALDER REACTIONS; INHIBITING GP120-CD4 BINDING; REENGINEERING VANCOMYCIN; STEREOCHEMICAL DETERMINATION; ANTIMITOTIC BICYCLIC PEPTIDES; RING-SYSTEM
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja3121394

Herein we report a systematic study of the Larock indole annulation designed to explore the scope and define the generality of its use in macrocyclization reactions, its use in directly accessing the chloropeptin I versus II DEF ring system as well as key unnatural isomers, its utility for both peptide-derived and more conventional carbon-chain based macrocycles, and its extension to intramolecular cyclizations with formation of common ring sizes. The studies define a powerful method complementary to the Stille or Suzuki cross-coupling reactions for the synthesis of cyclic or macrocyclic ring systems containing an embedded indole, tolerating numerous functional groups and incorporating various (up to 28-membered) ring sizes. As a result of the efforts to expand the usefulness and scope of the reaction, we also disclose a catalytic variant of the reaction, along with a powerful Pd2(dba)3-derived catalyst system, and an examination of the factors impacting reactivity and catalysis.