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Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed CyClick chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073-19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in CyClick of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre-organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the CyClick of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses CyClick reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of tunable amine-reactive electrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective probes for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins in different cell lines, and for the selective identification of lysines in the human proteome on a global scale.

Aldehyde decarbonylation is a vital chemical transformation in the synthesis of natural products. Nature accomplishes this process through a family of decarbonylase enzymes, while in the laboratory, harsh transition metals and elevated temperatures are required. Herein, we report a mild aldehyde decarbonylation reaction that exhibits exclusive selectivity for ortho -aldehydes during a tandem nitrile boronic acid cross-coupling reaction. A wide substrate scope is displayed that includes regioselective removal of the ortho -aldehyde from phenyl boronic acids in the presence of meta - or para -aldehydes. A mechanistic investigation of the observed regioselectivity for ortho -aldehydes by density functional theory (DFT) calculations shows that the CO ligand extrusion is energetically more favorable for the ortho position as compared to the para position. [ABSTRACT FROM AUTHOR]

Inspired by the enzyme lysyl oxidase, which selectively converts the side chain of lysine into allysine, an aldehyde‐containing post‐translational modification, we report herein the first chemical method for the synthesis of allysine by selective oxidation of dimethyl lysine. This approach is highly chemoselective for dimethyl lysine on proteins. We highlight the utility of this biomimetic approach for generating aldehydes in a variety of pharmaceutically active linear and cyclic peptides at a late stage for their diversification with various affinity and fluorescent tags. Notably, we utilized this approach for generating small‐molecule aldehydes from the corresponding tertiary amines. We further demonstrated the potential of this approach in generating cellular models for studying allysine‐associated diseases. [ABSTRACT FROM AUTHOR]

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The chemical modification of proteins in a site‐selective manner leads to many advances in various scientific fields. The major challenges with conventional N‐terminal bioconjugation techniques are the lack of universal sequence compatibility and poor mass‐detection sensitivity of the resulting bioconjugates. This approach efficiently analyzes proteolytic fragments and native proteins in a complex mixture. Multiple chemical steps are usually required for the site‐selective synthesis of bioconjugates with enhanced mass‐detection sensitivity. We present a single‐step, versatile strategy for the selective modification of protein N‐termini with mass boosters. The chemical tag enhances the peptide detection by multiple orders thus leading to the unambiguous analysis of the resulting bioconjugates. We demonstrate that tagging proteolytic fragments with mass sensitivity probes in a complex mixture improves the detection of resulting bioconjugates. [ABSTRACT FROM AUTHOR]

The emergence of cyclic peptides as pharmaceuticals has led to an eruption of new methodologies for macrocyclization. However, the cyclization of peptides at high concentrations presents a challenge due to the production of side products like dimers and oligomers. This factor is more pronounced with the cyclization of peptides composed of fewer than seven amino acids, thus has created a need for a new synthetic strategy. Herein, we will elucidate a new chemoselective method termed 'CyClick' that works in an exclusively intramolecular fashion preventing the formation of commonly occurring side products such as dimers and oligomers, even at relatively high concentration. 1 Introduction 2 Known Methodologies 3 Novel CyClick Chemistry 4 Conclusion and Outlook [ABSTRACT FROM AUTHOR]