Long‐Range Chemical Ligation from N→N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10‐ to 18‐Members

Abstract

Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.

Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology

“…This concept is often referred to as ‘entropic activation' 138 . Through a series of detailed mechanistic studies it has been determined that several factors are involved in the outcome of an S -to- N acyl transfer reaction, these include, ring-size of the TS, conformation, hydrogen-bonding, NH-π interactions, pH, solvent, reactivity/stability of thioester and structure of the AAs in the ring/near the ligation site 137 138 139 . In addition, the findings of AML have established that templating effects can assist the rate of the intramolecular reaction across a range of ring sizes 75 .…”

Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism

“…The N7 / N9 -transferrocenoylation in purines may be classified as an intramolecular acyl migration, which is of special importance in organic and medicinal chemistry. An acyl shift occurs frequently in carbohydrates, lipids, or peptides − and serves as a reaction channel in prodrug design and various synthetic strategies. − So far, however, only a few studies have coupled experimental and computational methods to clarify the underlying mechanism. In this work, a cluster of earlier relevant examples, including imidazole rings and benzotriazoles, , has been expanded to purines.…”

Expansion of Phosphane Treasure Box for Staudinger Peptide Ligation

“…8 To measure the conformer preorganization for the nucleophilic attack, the distance represented as d(N−C) between the N atom and the C atom is considered as the proximity function. 9 The preorganized conformers of A1-7m and B1-11m resulted 3.40 and 4.80 Å distances in 7-and 11-membered transition states, respectively. All thermochemical parameters (enthalpy: ΔH, temperature × entropy: TΔS, Gibbs free energy: ΔG) were also calculated along with transition-state reaction path sampling computations to verify the spontaneity of the reaction toward the formation of 6db (Table 3).…”

“…The established computational procedure consists of a complete conformational search, optimization of the conformer to conform the proximity function, and transition-state search studies, as validated in previous work . To measure the conformer preorganization for the nucleophilic attack, the distance represented as d (N–C) between the N atom and the C atom is considered as the proximity function . The preorganized conformers of A1-7m and B1-11m resulted 3.40 and 4.80 Å distances in 7- and 11-membered transition states, respectively.…”