High-valent FeIVO intermediates with a terminal metal–oxo moiety are key oxidants in many enzymatic and synthetic C–H bond oxidation reactions. While generating stable metal–oxo species for late transition metals remains synthetically challenging, notably, a number of high-valent non-oxo–metal species of late transition metals have been recently described as strong oxidants that activate C–H bonds. In this work, we obtained an unprecedented mononuclear CoIV–dinitrate complex (2) upon one-electron oxidation of its Co­(III) precursor supported by a tridentate dianionic N3 ligand. 2 was structurally characterized by X-ray crystallography, showing a square pyramidal geometry with two coordinated nitrate anions. Furthermore, characterization of 2 using combined spectroscopic and computational methods revealed that 2 is a low-spin (S = 1/2) Co­(IV) species with the unpaired electron located on the cobalt d z2 orbital, which is well positioned for substrate oxidations. Indeed, while having a high thermal stability, 2 is able to cleave sp3 C–H bonds up to 87 kcal/mol to afford rate constants and kinetic isotope effects (KIEs) of 2–6 that are comparable to other high-valent metal oxidants. The ability to oxidize strong C–H bonds has yet to be observed for CoIV–O and CoIIIO species previously reported. Therefore, 2 represents the first high-valent Co­(IV) species that is both structurally characterized by X-ray crystallography and capable of activating strong C–H bonds.

Direct peptide and protein activation is a challenging transformation because of the stabilizing effect of the amide group. While enzymes can be considered as prototypical systems that have evolved to achieve high selectivity and specificity, small-molecule catalysts that functionalize the amide group may accommodate a much larger selection of substrates but currently remain scarce. Here, by combining the desired features from both catalytic regimes we designed an artificial cyclodehydratase, a catalytic system for the site-selective modification of peptides and natural products by engrafting heterocycles into their scaffolds. The catalytic system features a molybdenum­(VI) center that was decorated with a sterically congested tripod ligand. The optimized catalyst can introduce azolines into small molecules, natural products, and oligopeptides with high efficiency and minimal waste. We further demonstrate the utility of the new protocol in the direct functionalization of a single amide group in the presence of up to seven other chemically similar positions and in the direct conversion of these groups into amines and thioamides. This new mechanistic paradigm may address an unmet need for a general method for the selective and sustainable functionalization of peptides and natural products.

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

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Oxazolines and thiazolines are important constituents of bioactive natural products and pharmaceuticals. Here, we report the development of an effective and practical method of oxazoline and thiazoline formation, which can facilitate the synthesis of natural products, chiral ligands, and pharmaceutical intermediates. This method capitalized on a Mo(VI) dioxide catalyst stabilized by substituted picolinic acid ligands, which is tolerant to many functional groups that would otherwise be sensitive to highly electrophilic alternative reagents.