N-Heterocyclic Carbene-Catalyzed Random Copolymerization of N-Carboxyanhydrides of α-Amino Acids

Synthetic polypeptides prepared from N-carboxyanhydrides (NCAs) of α-amino acids are useful for elucidating the relationship between the primary structure of natural peptides and their immunogenicity. In this study, complex copolypeptide sequences were prepared using a recently developed technique; specifically, the random copolymerization of l-alanine NCA with NCAs of l-glutamic acid 5-benzylester (Bn-Glu NCA), S-benzyl-cysteine (Bn-Cys NCA), O-benzyl-l-serine (Bn-Ser NCA), and l-phenylalanine (Phe NCA) was performed using N-heterocyclic carbene (NHC) catalysts. The NHC-initiated Ala NCA/Bn-Glu NCA and Ala NCA/Bn-Cys NCA copolymerization reactions achieved 90% conversion within 30 min. The reactivity ratio values estimated using the Kelen and Tüdos method show that poly(Bn-Glu-co-Ala) and poly(Bn-Cys-co-Ala) have random repeating units with rich alternating sequences, whereas poly(Bn-Ser-co-Ala) and poly(Phe-co-Ala) contain a larger proportion of Ala-repeating units than Bn-Ser and Phe in random placement.

A moisture-tolerant route to unprotected α/β-amino acid N-carboxyanhydrides and facile synthesis of hyperbranched polypeptides

A great hurdle in the production of synthetic polypeptides lies in the access of N-carboxyanhydrides (NCA) monomers, which requires dry solvents, Schlenk line/gloveboxe, and protection of side-chain functional groups. Here we report a robust method for preparing unprotected NCA monomers in air and under moisture. The method employs epoxy compounds as ultra-fast scavengers of hydrogen chloride to allow assisted ring-closure and prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and functional group tolerance of the method are demonstrated by the facile synthesis of over 30 different α/β-amino acid NCAs, including many otherwise inaccessible compounds with reactive functional groups, at high yield, high purity, and up to decagram scales. The utility of the method and the unprotected NCAs is demonstrated by the facile synthesis of two water-soluble polypeptides that are promising candidates for drug delivery and protein modification. Overall, our strategy holds great potential for facilitating the synthesis of NCA and expanding the industrial application of synthetic polypeptides.

Strategies for the Development of pH-Responsive Synthetic Polypeptides and Polymer-Peptide Hybrids: Recent Advancements

Synthetic polypeptides and polymer-peptide hybrid materials have been successfully implemented in an array of biomedical applications owing to their biocompatibility, biodegradability and ability to mimic natural proteins. In addition, these materials have the capacity to form complex supramolecular structures, facilitate specific biological interactions, and incorporate a diverse selection of functional groups that can be used as the basis for further synthetic modification. Like conventional synthetic polymers, polypeptide-based materials can be designed to respond to external stimuli (e.g., light and temperature) or changes in the environmental conditions (e.g., redox reactions and pH). In particular, pH-responsive polypeptide-based systems represent an interesting avenue for the preparation of novel drug delivery systems that can exploit physiological or pathological pH variations within the body, such as those that arise in the extracellular tumour microenvironment, intracellularly within endosomes/lysosomes, or during tissue inflammation. Here, we review the significant progress made in advancing pH-responsive polypeptides and polymer-peptide hybrid materials during the last five years, with a particular emphasis on the manipulation of ionisable functional groups, pH-labile linkages, pH-sensitive changes to secondary structure, and supramolecular interactions.

A Robust, Open-Flask, Moisture-Tolerant, and Scalable Route to Unprotected α/β-Amino Acid N-Carboxyanhydrides

Synthetic polypeptides, commonly prepared by the ring-opening polymerization (ROP) of amino acid N-carboxyanhydrides (NCA), are a family of biomimetic materials with vast biomedical applications. A great hurdle in the pro-duction of synthetic polypeptides is the synthesis of NCA, which requires ultra-dry solvents, Schlenk line/gloveboxes, and the protection of sidechain functional groups. Herein, we report a robust and scalable new method for the production of unpro-tected NCA monomers in air and under moisture. The method employs propylene oxide or epichlorohydrin as an inexpensive and ultra-fast scavenger of hydrogen chloride to prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and outstanding functional group tolerance of the method are demonstrated by the successful synthesis of more than 30 different NCAs, including many otherwise inaccessible compounds with reactive functional groups (e.g. hy-droxyl, thiol, and carboxylic acid), at high yield and up to ten-gram scale. The scope of the method can be further extended to various α-hydroxyl acid O-carboxyanhydrides (OCA) and β-amino acid NCAs (βNCA). Given these merits, our strategy holds great potential for revolutionizing the synthesis of NCA and polypeptides, and dramatically expanding the industrial application of synthetic polypeptides

A Robust, Open-Flask, Moisture-Tolerant, and Scalable Route to Unprotected α/β-Amino Acid N-Carboxyanhydrides

Synthetic polypeptides, commonly prepared by the ring-opening polymerization (ROP) of amino acid N-carboxyanhydrides (NCA), are a family of biomimetic materials with vast biomedical applications. A great hurdle in the pro-duction of synthetic polypeptides is the synthesis of NCA, which requires ultra-dry solvents, Schlenk line/gloveboxes, and the protection of sidechain functional groups. Herein, we report a robust and scalable new method for the production of unpro-tected NCA monomers in air and under moisture. The method employs propylene oxide or epichlorohydrin as an inexpensive and ultra-fast scavenger of hydrogen chloride to prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and outstanding functional group tolerance of the method are demonstrated by the successful synthesis of more than 30 different NCAs, including many otherwise inaccessible compounds with reactive functional groups (e.g. hy-droxyl, thiol, and carboxylic acid), at high yield and up to ten-gram scale. The scope of the method can be further extended to various α-hydroxyl acid O-carboxyanhydrides (OCA) and β-amino acid NCAs (βNCA). Given these merits, our strategy holds great potential for revolutionizing the synthesis of NCA and polypeptides, and dramatically expanding the industrial application of synthetic polypeptides