Peptide based macrocycles have found wide application, from therapeutic agents to biomaterials. Among various strategies for generating macrocyclic peptides, creation of side-chain to side-chain bridges has the advantage of not disrupting potential interaction between the N- or C-termini and the target receptor. Depending on the functional groups in the side chains, the established macrocyclization reactions have included ring-closing metathesis, amide-coupling reactions, and azide-alkyne cycloadditions. The use of transition-metal catalysts for C�C bond formation between aromatic rings constitutes an attractive way to construct biaryl-macrocycles, which represent a carbogenic fusion of naturally occurring aromatic amino acid side-chains. Here we present a macrocyclization between the side chains of tryptophan and phenylalanine derivatives through a palladium-catalyzed C�H activation reaction. This macrocyclization features a chemoselective C�H arylation of indole derivatives. The scope and the future direction of this chemistry will be discussed.                                                                                              

Peptide macrocyclization via Pd-catalyzed chemoselective indole C-2 arylation

243rd National Meeting (2012)

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