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

Convenient route to Fmoc-homotyrosine via metallaphotoredox catalysis and its use in the total synthesis of anabaenopeptin cyclic peptides

“…50 We found another precedent of a photoredox-mediated reaction on an Fmoc amino acid side chain, namely the decarboxylative borylation of an N -Fmoc protected redox-active ester derivative of aspartic acid reported by Walczak and coworkers. 51…”

“…50 We found another precedent of a photoredox-mediated reaction on an Fmoc amino acid side chain, namely the decarboxylative borylation of an N-Fmoc protected redox-active ester derivative of aspartic acid reported by Walczak and coworkers. 51 Starting from our initial conditions, the impact of various parameters on the coupling yield was investigated. Table 1 highlights some results of our optimization efforts.…”

Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation

“…An alternative approach is the transition metal-catalyzed cross-coupling reactions between an aryl halide and an Ala M reagent (Fig. 2A) (24)(25)(26). While this reaction offers reliable access to L-aryl alanine moieties, it still suffers from limitations such as the labile or difficult-to-synthesize nature of some Ala M reagents.…”

Desulfurative Borylation of Small Molecules, Peptides, and Proteins

“…For most samples, a loss of one or two molecules of H 2 O was recorded. These observations are consistent with our previous work and other published results showing a formation of so-called Wulff boronates with the neighboring amide groups . However, these equilibria bear no consequence for the downstream applications, and the borylation products can be converted into serine with NaBO 3 or undergo conjugation with pinane­diol with excellent chemo­selectivity (for details, see the SI).…”

“…Organoboron reagents occupy a privileged role in synthetic chemistry due to their broad utility in cross-coupling reactions and multitude of stereo­selective transformations. , There is also a growing interest to incorporate nontraditional isosteres such as boronic acids into peptides, proteins, carbohydrates, , and polymers − to create novel therapeutic leads − and biomolecular sensing tools, and in bioconjugation with bioactive cargo (Scheme A) . In contrast to many other main group elements, boron-containing natural products are often characterized by a labile B–O linkage, , and the C–B bond common to many organic molecules is unprecedented.…”