Synthesis of Peptides by Silver‐Promoted Coupling of Carboxylates and Thioamides: Mechanistic Insight from Computational Studies

Abstract

The mechanism of the recently described N→C direction peptide synthesis through silver-promoted coupling of N-protected amino acids with thioacetylated amino esters was explored by using density functional theory. Calculation of the potential energy surfaces for various pathways revealed that the reaction proceeds through silver-assisted addition of the carboxylate to the thioamide, which is followed by deprotonation and silver-mediated extrusion of sulfur as Ag2 S. The resulting isoimide is the key intermediate, which subsequently rearranges to an imide through a concerted pericyclic [1,3]-acyl shift (O-sp(2) N 1,3-acyl migration). The proposed mechanism clearly emphasises the requirement of two equivalents of Ag(I) and basic reaction conditions, which is in full agreement with the experimental findings. Alternative rearrangement pathways involving only one equivalent of Ag(I) or through O-sp(3) N 1,3-acyl migration can be excluded. The computations further revealed that peptide couplings involving thioformamides require significant conformational changes in the intermediate isoformimide, which slow down the rearrangement process.

Rapid, Traceless, AgI‐Promoted Macrocyclization of Peptides Possessing an N‐Terminal Thioamide

“…[24] We propose that the same process in an intramolecular reaction results in aAg I -templated cyclization (Figure 4), reminiscent of the metal-ion-templated cyclization reactions of peptide thioesters. [24] We propose that the same process in an intramolecular reaction results in aAg I -templated cyclization (Figure 4), reminiscent of the metal-ion-templated cyclization reactions of peptide thioesters.…”

“…Our previous mechanistic studies of the intermolecular reaction showed that Ag I coordinates to both the carboxylate and the thioamide. [24] We propose that the same process in an intramolecular reaction results in aAg I -templated cyclization (Figure 4), reminiscent of the metal-ion-templated cyclization reactions of peptide thioesters. [10] Importantly,inthis process the Ag I both chemoselectively activates the thioamide to nucleophilic attack by the carboxylate,a nd templates the cyclization by bringing the N-a nd C-termini in close proximity,t hereby overcoming the entropic barrier to cyclization resulting in af ast reaction.…”

“…However,cyclization of linear peptides is frequently plagued by epimerization, cyclodimerization, and the formation of higher oligomers. [23,24] This thioamide-directed peptide synthesis proceeds through the generation of an isoimide intermediate,w hich can rearrange to an imide via an O!Nacyl transfer (Scheme 1a). [20][21][22] Our group has recently developed an ew method for peptide synthesis through the Ag I -promoted reaction of thioamides with peptide C-terminal carboxylic acids,w hich has been exploited in the epimerization-free synthesis of peptides in the N!Cd irection (Scheme 1b).…”

“…[20][21][22] Our group has recently developed an ew method for peptide synthesis through the Ag I -promoted reaction of thioamides with peptide C-terminal carboxylic acids,w hich has been exploited in the epimerization-free synthesis of peptides in the N!Cd irection (Scheme 1b). [23,24] This thioamide-directed peptide synthesis proceeds through the generation of an isoimide intermediate,w hich can rearrange to an imide via an O!Nacyl transfer (Scheme 1a). Selective imide hydrolysis then generates the amide bond.…”

Rapid, Traceless, AgI‐Promoted Macrocyclization of Peptides Possessing an N‐Terminal Thioamide

“…Our group has recently developed a new method for peptide synthesis through the Ag I ‐promoted reaction of thioamides with peptide C ‐terminal carboxylic acids, which has been exploited in the epimerization‐free synthesis of peptides in the N→C direction (Scheme b) . This thioamide‐directed peptide synthesis proceeds through the generation of an isoimide intermediate, which can rearrange to an imide via an O→N acyl transfer (Scheme a).…”