Synthesis of Peptide-Based Polymers by Microwave-Assisted Cycloaddition Backbone Polymerization

Abstract

The optimized reaction conditions for the Cu(I)-catalyzed N-->C polymerization of azido-phenylalanyl-alanyl-propargyl amide to yield either high molecular weight linear polymers or medium-sized cyclic polymers is described. These reaction conditions will be applied to tailor the synthesis, properties, and structure of biologically relevant peptide-based biopolymers.

Application of the 1,3‐Dipolar Cycloaddition Reaction in Chemical Biology: Approaches Toward Multivalent Carbohydrates and Peptides and Peptide‐Based Polymers

“…Microwave irradiation was used to ensure a complete modification of the alkyne endgroups [31]. Via this approach, divalent (33, 37 -40, 43, 45, 46, 48), tetravalent (34,41,44,47,49), octavalent (35,42), and hexadecavalent (36) dendrimeric peptides were synthesized. Not only small (di)peptide-based azides but also unprotected biologically relevant larger (e.g., Leu-enkephalin 29, part of the anti-microbial peptide magainin 30, a fibronectin active fragment 31), even cyclic, azido peptides, e.g., an a V b 3 integrin binding RGD-containing peptide 32 have been efficiently converted into the corresponding dendrimeric cycloaddition products, as shown in Figure 4.…”

“…In most of the cases, (partially) protected building blocks are required and after the synthesis of the polymer, the protecting groups have to be removed, which is not a trivial task. The possibility of the chemoselective azide -alkyne coupling in the presence of other unprotected functional groups and the topological similarities between peptide amides and 1,2,3-triazoles [34] made us decide to explore the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction for the synthesis of peptide-based polymers [35]. In our studies, we used model dipeptide azido-phenylalanyl-alanyl-propargyl amide 51 (Scheme 3) which could be efficiently converted into high molecular weight amino acid-based polymers (up to 45 kDa).…”

A Modular Approach to Functionalized and Expanded Crown Ether Based Macrocycles Using Click Chemistry

“…Previous studies regarding the effect of monomer dilution during the CuAAC step-growth polymerization of a-azide-w-alkyne monomers have shown that yields of monocyclization as high as 60 % could be attained using monomer concentrations of about 1 mm. [14] To improve the yield and efficiency of macrocycle formation, cyclization experiments were performed using a peristaltic pump for the controlled addition of monomer solutions to a solution of the catalytic system maintained at 60 8C. In this way, the reaction mixture contains a relatively dilute solution of the monomer at all times, and the monomer is exposed to a much higher concentration of catalyst to ensure a fast CuAAC intramolecular reaction.…”

Click Chemistry: A Powerful Tool to Create Polymer‐Based Macromolecular Chimeras

“…The selectivity of this reaction proved to be a striking consequence of the mechanistic constraints posed by the 1,3-copper(I) catalyzed cycloaddition itself. Following the bibliography reports indicating that most of the peptide-based biopolymers derive their structural, mechanical, and biological properties from sequential repetitions on their backbone (e.g., collagens, elastin and spider silk, antifreeze proteins, mussel glue, and reflectins), [43] in a study aimed to mimic such natural peptide biopolymers with repetitive sequences, Liskamp and coworkers [44] developed a method to prepare high molecular weight linear or medium-sized cyclic polypeptides based on click chemistry ( Figure 1C). Their work relied on the polymerization of azido-phenylalanyl-alanyl-propargyl amides by a microwave-assisted 1,3-dipolar polycycloaddition reaction.…”

“…It was for example proven that microwave heating was in general superior to conventional heating for direction of the reaction outcome in such high molecular weight polymers. Following the same approach, Angell and Burgess [46] achieved the synthesis of SH2 domain-binding peptides and their open-chain analogs by reacting with monomers containing a single azide or alkyne group each [46] while van (C) Liskamp and coworkers [44] approach to linear and cyclic polypeptides. Reaction using CuSO 4 /Na ascorbate or Cu(OAc) led predominantly to linear polymerization, while with lower monomer ratio and Cu(OAc), cyclic products were obtained.…”