Umpolung Ala^B Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**

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 solidphase 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 Pdcatalyzed reactions, including CÀ 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.Peptides and proteins are important targets in modern drug discovery because of their ease of synthesis, low toxicity, and target selectivity. [1] Native peptides, however, can often show low bioavailability and short lifetimes rendering them suboptimal for clinical applications. [2] To address these challenges, non-proteogenic amino acids (NPAAs), a class of amino acids not encoded in the human genome, emerged as a valuable tool to increase structural diversity and improve pharmacokinetic properties. [3] Several strategies to access NPAAs are known including the Strecker reaction, [4] asymmetric hydrogenation, [5] conjugate addition, [6] biotransformations, [7] photoredox cross-electrophile coupling, [8] CÀ H activation, [9] and phase-transfer alkylation. [10] Access to unnatural surrogates through any of these strategies complements studies on selective modifications of biologics that can be achieved through various handles that can enable downstream functionalizations (Scheme 1A). One promising approach that can avoid competing reactions with innate groups are transformations based on umpolung of reactivity. [11] We recently reported the synthesis and applications of Ala Sn reagents in the form of carbastannatrane 1, [12] a member of a larger group of reagents where alanine's β-carbon is substituted with a metal or metalloid (Scheme 1B). Ala M reagents represent a novel type of synthons that can be engaged in cross-coupling reactions through a reversal of polarity at the β-carbon.From a conceptual standpoint, these reagents can give rise to native as well as unnatural amino acids based on a formal alanine derivatization. Several members of this family are known including organogermanium Ala Ge 2, [13] organoboron Ala B 3, [14] organosilane Ala Si 4 [14l, 15] organozinc Ala Zn 5, [16] organolithium, [14e,g] and organonickel Ala Ni[17] derivatives