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We report a minimalist gaseous sulfonyl-chloride-derived reagent for multicomponent bioconjugation with amine, phenol, or aniline reagents to afford urea or carbamate products. With the utilization of a gas-phase reagent for a reaction mediated by metal ions, a variety of biologically relevant molecules, such as saccharide, poly(ethylene glycol), fluorophore, and affinity tag, can be efficiently cross-linked to the N terminus or lysine side-chain amines on natural polypeptides or proteins. 

Pyroglutamate is a cyclic N-terminal posttranslational modifica-tion that occurs in both proteins and peptide hormones. The prevalence and biological roles of pyroglutamate are little under-stood, in part due to limited tools to identify, quantify, and ma-nipulate its pyrrolidinone structure. Selective modification of pyroglutamate residues in complex polypeptides may provide unique tools to better understand its biological roles, and to al-low late-stage diversification of biologically active pyrogluta-mate-containing sequences. This work describes a copper-catalyzed N–H cross-coupling of unprotected peptides that is selective for N-terminal pyroglutamate residues. The reaction is operationally simple under mild conditions, and tolerates almost all canonical residues. Mechanistic studies point to a key role for a multidentate copper-binding mode of the extended polypeptide structure in delivering the observed reactivity. The reaction al-lows direct labeling and identification of a pyroglutamate hormone present in porcine intestinal extracts. 

Abstract Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal‐mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting‐group strategies. 

Proximity-induced methodologies for peptide and protein modification have been developed using recognition elements like inhibitors, antibodies, or affinity tags on amino acids. However, the recognition a of saccharides for chemical modification remains widely unexplored. Recent studies exploring boronic acids and their derivatives have shown their alluring capabilities as selective molecular recognition elements for saccharides, providing the first insight into a recognition methodology for this moiety. Herein is described the discovery of catalytic proximity-induced rhodium(II) methodology for covalent modification of glycopeptides using boronic acids as a saccharide recognition element. 

Sulfoximines are emerging moieties for medicinal and biological chemistry, due in part to their efficacy in selective inhibition of amide-forming enzymes such as γ-glutamylcysteine synthetase. While small-molecule sulfoximines such as methionine sulfoximine (MSO) and its derivatives are well studied, structures with methionine sulfoximine residues within complex polypeptides have been generally inaccessible. This paper describes a straightforward means of late-stage one-step oxidation of methionine residues within polypeptides to afford NH-sulfoximines. We also present chemoselective subsequent elaboration, most notably by copper( ii )-mediated N–H cross-coupling at methionine sulfoximine residues with arylboronic acid reagents. This development serves as a strategy to incorporate diverse sulfoximine structures within natural polypeptides, and also identifies the methionine sulfoximine residue as a new site for bioorthogonal, chemoselective bioconjugation.