Peptide macrocyclization is often a slow process, plagued by epimerization and cyclodimerization. Herein, we describe a new method for peptide macrocyclization employing the AgI‐promoted transformation of peptide thioamides. The AgI has a dual function: chemoselectively activating the thioamide and tethering the N‐terminal thioamide to the C‐terminal carboxylate. Extrusion of Ag2S generates an isoimide intermediate, which undergoes acyl transfer to generate the native cyclic peptide, resulting in a rapid, traceless macrocylization process. Cyclic peptides are furnished in high yields within 1 hour, free of epimerization and cyclodimerization.

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The impact of geometrically constrained cis α,β-unsaturated γ-amino acids on the folding of α,γ-hybrid peptides was investigated. Structure analysis in single crystals and in solution revealed that the cis carbon-carbon double bonds can be accommodated into the 12-helix without deviation from the overall helical conformation. The helical structures are stabilized by 4→1 hydrogen bonding in a similar manner to the 12-helices of β-peptides and the 310 helices of α-peptides. These results show that functional cis carbon-carbon double bonds can be accommodated into the backbone of helical peptides.

Dityrosine cross-linking of Aβ peptides and α-synuclein is increasingly becoming recognized as a biomarker of neuropathological diseases. However, there remains a need for the development of analytical methods that enable the specific and selective identification of dityrosine cross-linked proteins and peptides in complex biological samples. Here, we report that the gas-phase fragmentation of protonated dityrosine cross-linked peptides under ultraviolet photodissociation (UVPD) tandem mass spectrometry (MS/MS) conditions results in the cleavage across C α and C β atoms of the dityrosine residue. This C α −C β cleavage in UVPD−MS/MS results in the formation of diagnostic pairs of product ions, providing information on the two individual peptides involved in the cross-linking, resolving the intrinsic "n 2 problem" plaguing the identification of this post-translational modification (PTM) by tandem mass spectrometry. Sequencing of a heterodimeric dityrosine cross-linked peptide was demonstrated using hybrid UVPD−MS/MS and CID−MS 3 on a diagnostic pair of product ions. In combination with dedicated MS−cleavable MS n software, UVPD−MS n therefore provides an avenue to selectively discover and describe dityrosine crosslinked peptides. Additionally, observation of dityrosine-specific "reporter ions" at m/z 240.1019 and m/z 223.0752 in UVPD− MS/MS will be useful for the validation of the dityrosine cross-linked peptides.

The AgI‐promoted reaction of thiolactams with N‐Boc amino acids yields an N‐(α‐aminoacyl) lactam that can rearrange through an acyl transfer process. Boc‐deprotection results in convergence to the ring‐expanded adduct, thereby facilitating an overall insertion of an amino acid into the thioamide bond to generate medium‐sized heterocycles. Application to the site‐specific insertion of amino acids into cyclic peptides is demonstrated.