Umpolung Ala B Reagents for the Synthesis of Non-Proteogenic Amino Acids, Peptides and Proteins.

Non-proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala B can serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala B from redox-active esters of aspartic acid resulting in a series of β-boronoalanine derivatives. Next, we show that Ala B can be integrated into automated oligopeptide solid-phase synthesis. Ala B is compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of Ala B -containing ubiquitin. Furthermore, Ala B reagents participate in Pd-catalyzed reactions, including C-C cross-couplings and macrocyclizations. Taken together, Ala B synthons are practical reagents to access modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.