Umpolung Ala <sup>B</sup> Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**
Feng Zhu, Eric J. Miller, Wyatt C. Powell, Kelly Johnson, Alexander Beggs, Garrett E. Evenson, Maciej A. Walczak
Abstract
Abstract 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.