New methods for peptide modification are in high demand in drug discovery, chemical biology and materials chemistry; methods that modify natural peptides are particularly attractive. A Pd-catalyzed, C-H functionalization protocol for the olefination of phenylalanine residues in peptides is reported, which is compatible with common amino acid protecting groups, and the scope of the styrene reaction partner is broad. Bidentate coordination of the peptide to the catalyst appears crucial for the success of the reaction.
There is high-demand for new methods to modify peptides, for application in drug discovery and biomedicine. A C-H functionalization protocol for the olefination of tryptophan residues in peptides is described. The modification is successful for Trp residues at any position in the peptide, has broad scope in the styrene coupling partner, and offers opportunities for conjugating peptides with other biomolecules. For peptides containing both Trp and Phe, directing group manipulation enables full-control of residue selectivity. Peptide modification has a critical role to play in drug discovery, the diagnosis of disease, and the understanding of biological mechanism and function. 1,2 As examples, peptidefluorophore conjugates, 3-5 which enable the imaging of biological systems, have been used to diagnose infection, 6,7 and to aid surgery. 8,9 In drug discovery, where peptide therapeutics often have higher potency and target specificity than small molecule drugs, 10-12 synthetic peptide modification can provide necessary improvements to drug stability, cell penetration and oral bioavailability. 13-16 Of the large number of methods that have been developed for the modification of peptides, 2,17 most rely upon the reactions of heteroatoms, which may themselves be crucial to structure and biological function. 18,19 Alternatively, peptides and proteins have been modified at carbon atoms by metalcatalyzed cross-coupling reactions, but these methods require the incorporation of non-natural amino acids. 20-22 Consequently, new methods of peptide modification that operate at carbon atoms and in native peptides are needed. To achieve this goal, there has been rapid progress in developing methods for the C-H functionalization of peptides. 23-37 For example, C(sp 3)-H functionalization of alanine residues can give rise to phenylalanine derivates. 25 C(sp 2)-H functionalization of aromatic amino acids has focussed almost entirely on tryptophan (Trp) residues, that have been modified using arylation, alkynylation and allylation, Scheme 1A. 26-35 In addition , the modification of phenylalanine (Phe) residues in peptides has recently been achieved through C-H olefination, Scheme 1B. 36-38 Scheme 1. C-H functionalization of aromatic amino acids in peptides.
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