Umpolung AlaB 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 and used as mechanistic tools in chemical biology. Here, we show that functionalized amino acid synthons in the form of AlaB 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 AlaB from redox-active esters of aspartic acid resulting in a series of beta-boronoalanine derivatives. Next, we show that AlaB can be integrated into automated solid-phase synthesis of oligopeptides and proteins. AlaB is compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of boronoalanine-modified ubiquitin (Phe4-AlaB). Furthermore, AlaB reagents participate in Pd-catalyzed reactions, including C(sp3)-C(sp2) cross-couplings and macrocyclizations. Taken together, AlaB synthons are practical reagents to access non-natural amino acids, modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.