Ligand-Enabled Selective Coupling of MIDA Boronates to Dehydroalanine-Containing Peptides and Proteins

α,β-dehydroalanine (ΔAla) is a uniquely reactive nonproteinogenic amino acid often employed for the late-stage functionalization of peptides, natural products (NPs), and proteins. The modification of ΔAla is a powerful method for the semisynthetic engineering of NPs and for post-translational protein mutagenesis. Numerous enabling ΔAla modification techniques have been developed over the years, but most state-of-the-art approaches furnish product mixtures detrimental in many applications. Here, we report a Pd(II)-mediated coupling reaction between aryl N-methylimidodiacetic acid boronates and ΔAla-containing peptides and proteins which yields ΔzPhe coupling products with high selectivity. The coupling proceeds in water under ambient conditions (37 °C, <24 h) and without the exclusion of oxygen using fully unprotected substrates. The speed and high selectivity of the reaction is enabled by the use of N,N'-ethylene-bis-^Lthreonine as a Pd(II) ligand. We utilize this chemistry to selectively functionalize a variety of oligopeptides, NP-like compounds, and intact proteins. Finally, we show that the coupling reaction can be readily adapted to modify in vitro translated peptides by devising a platform for the chemoribosomal synthesis of ΔzPhe-containing structures. Altogether, our chemistry provides a powerful tool for the selective late-stage functionalization of ΔAla in peptides and proteins.