Accelerated Submonomer Solid-Phase Synthesis of Peptoids Incorporating Multiple Substituted N-Aryl Glycine Monomers

Abstract

N-Aryl glycines are a chemically diverse class of peptoid monomers that have strong structure-inducing propensities. Yet their use has been limited due to the sluggish reactivity of the weakly nucleophilic aniline submonomers. Here, we report up to a 76-fold rate acceleration of the displacement reaction using aniline submonomers in solid-phase peptoid synthesis. This is achieved by adding halophilic silver salts to the displacement reaction, facilitating bromide abstraction and AgBr precipitation. Mechanistic insight derived from analysis of a series of 15 substituted anilines reveals that the silver-mediated reaction proceeds through a transition state that has considerably less positive charge buildup on the incoming nucleophile and an enhanced leaving group. This straightforward enhancement to the submonomer method enables the rapid room temperature synthesis of a wide variety of N-aryl glycine-rich peptoid oligomers, possessing both electron-withdrawing and -donating substituents, in good yields.

On‐resin N‐terminal peptoid degradation: Toward mild sequencing conditions

“…Of note, analysis of Nph-terminated peptoid was complicated by air oxidation and degradation of the peptoid over time. 10 As expected, deletion of the trans-inducing Nph residue was sluggish, providing the desired truncated tetrapeptoid in only 17% conversion (Tables I and II, 13d). A 24% drop in crude purity was observed for the peptoid containing a Nspe residue at the second position (R 2 ) (Tables I and II, 13e), where the sterically encumbered cis-inducing Nspe residue might be preventing efficient formation of the cyclic intermediate.…”

“…We next tried to perform a second consecutive N ‐terminal degradation reaction cycle. In this case, the bromoacetylation step was performed 2 x 20 min in order to ensure that the AgBr precipitate from the first degradation cycle was fully dissolved and washed away . Following treatment of the resin‐bound bromoacetylated tetrapeptoids with silver perchlorate to give tripeptoid 15 , a drop of ∼23% in purity was observed on average (Table ).…”

“…We recently reported a way to accelerate displacement reactions in submonomer peptoid synthesis using aniline weak nucleophiles, where halophilic silver salts were employed to promote halide abstraction and formation of an AgBr precipitate. 10 In the course of that work, we found that the treatment of resin-bound, bromoacetylated peptoids with AgClO 4 solutions in the absence of an amine submonomer leads to onresin truncation of the N-terminal residue via an intramolecular cyclization reaction, generating an N-substituted morpholine-2,5-dione byproduct (Scheme 1b). These mild reaction conditions allow the N-terminal degradation of peptoid SCHEME 1 (a) Edman degradation conditions 1 vs. (b) a mild approach for N-terminal degradation using silver salts.…”

Polypeptoids synthesis based on Ugi reaction: Advances and perspectives

“…Typically, two different synthetic strategies toward polypeptoids are possible: iterative submonomer route and ring‐opening polymerization (ROP) of N ‐substituted α‐amino acid‐ N ‐carboxyanhydrides (NNCAs) . Polypeptoids with absolute monodispersity and controlled sequence can be harvested by submonomer approach.…”

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

“…Moreover, it is possible to carry out their large-scale synthesis in a cost effective way than peptides [3]. Also, the rapid room temperature synthesis of a wide variety of N-aryl glycine-rich peptoid oligomers with both electron-withdrawing and donating substituents is possible in good yields through silver-mediated reactions [4]. Thus, peptoids are extensively used as peptide mimics particularly of antimicrobial peptides [5][6][7], antibacterial magainin peptides [8] and lung surfactant proteins [9].…”