Suzuki-Miyaura Diversification of Amino Acids and Dipeptides in Aqueous Media

• Published in: ChemCatChem 2015-07, Vol.7 (14), p.2055-2070
• Main Authors: Willemse, Tom, Van Imp, Karolien, Goss, Rebecca J. M., Van Vlijmen, Herman W. T., Schepens, Wim, Maes, Bert U. W., Ballet, Steven
• Format: Article
• Language: English
• Subjects: Amino acids; Bacteriology; CC coupling; Diversification; homogenous catalysis; palladium; peptides
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.201500190

The Suzuki–Miyaura derivatisation of free amino acids, peptides and proteins is an attractive area with considerable potential utility for medicinal chemistry and chemical biology. Here we report the modification of unprotected and Boc‐protected aromatic amino acids and dipeptides in aqueous media, enabling heteroarylation and vinylation. We systematically investigate the impact of the peptide backbone and adjacent amino acid residues upon the reaction. Our studies reveal that although asparagine and histidine hinder the reaction, by utilising dppf, a ferrocene‐based bidentate phosphine ligand, cross coupling of halophenylalanine or halotryptophan adjacent to such a residue could be enabled. Our studies reveal dppf to have good compatibility with all unprotected, proteinogenic amino acid side chains. Get down and derivatise! The palladium‐catalysed Suzuki–Miyaura derivatisation of (un)protected Phe or Trp, and peptide substrates containing halogenated Phe or Trp, is performed via use of various water‐compatible catalytic systems. By mimicking the natural aqueous environment of peptides, halogenated moieties are transformed to a variety of (hetero)aryl and vinyl subtituents.