Ring-opening polymerization (ROP) of N-carboxyanhydrides (NCA) is an invaluable tool for preparing synthetic polypeptides and polypeptoids. They are typically synthesized in a controlled manner using primary amines as initiators, which is also the main approach for producing hybrid block copolymers, where various amino-end-group functionalized macroinitiators are used. This process is straightforward for linear block copolymers; however, synthesizing more complex polymer architectures, such as miktoarm stars, still requires the use of protecting groups, as the coexistence of different functional groups is unavoidable. To prepare AB2-type amphiphilic miktoarm stars consisting of one hydrophilic arm (A) and two hydrophobic arms (B), we used a heterofunctional core as a multifunctional initiator. The hydroxyl group of the initiator was used to initiate the ROP of propylene oxide (PO) to form the hydrophobic arms B, while the hydrophilic block A was prepared by ROP of sarcosine NCA using the amine group for ROP initiation. The main challenge was introducing the primary amine functionality into the polyether structure. To address this, we have recently shown that amino-functionalized polyethers can be readily prepared in the presence of classic carbamate-based amino-protecting groups (Boc and Cbz) by using a Lewis acid-excess two-component organocatalytic system [1]. Despite the higher intrinsic acidity of the carbamate group compared to the hydroxyl group, it does not interfere with the polymerization due to an acidity-reversing effect of the catalyst, which allows site-specific ethoxylation to proceed exclusively from the hydroxyl group. This demonstrates that fully controlled polymerization of epoxides can be achieved even in the presence of acidic protons, greatly facilitating the preparation of hybrid block copolymers.

On the other hand, ROP can also be used to prepare various cross-linked synthetic polypeptides, where control over molecular weight and chain-end fidelity is less important, but controlling the rate of polymerization is crucial. By performing ROP in oil-in-oil high internal phase emulsions (HIPE), we prepared macroporous cross-linked synthetic polypeptide polyHIPE scaffolds, where experimental conditions were carefully tuned to prevent scaffold foaming due to CO2 evolution [2]. By deprotecting the corresponding polypeptide scaffolds, we prepared stimuli-responsive polypeptide hydrogels with fully preserved polyHIPE morphology [3]. The hydrogels exhibit pH-dependent behavior, which can be modulated, along with their mechanical properties, by changing the chemical composition of the polypeptides. We discovered that the most commonly used L-cystine NCA cross-linker readily undergoes undesired decomposition side reactions, such as β-elimination and formation of 2,5-diketopiperazine, which can be completely avoided when the analogous L-homocystine NCA is used instead [4]. Furthermore, we developed a photochemical approach for ROP of NCA to prepare covalently cross-linked synthetic polypeptide gels using a photobase and light, which offers excellent spatial and temporal control [5].

References

1- U. Češarek, L. Liu, Q. Chen, T. Wen, E. Žagar, J. Zhao, D. Pahovnik J. Am. Chem. Soc. 2025, 6, 5189.

2- O.C. Onder, P. Utroša, S. Caserman, M. Podobnik, M. Tušek-Žnidarič, J. Grdadolnik, S. Kovačič, E. Žagar, D. Pahovnik Polym. Chem. 2020, 11, 4260.

3- O.C. Onder, P. Utroša, S. Caserman, M. Podobnik, E. Žagar, D. Pahovnik Macromolecules 2021, 54, 8321.

4- P. Utroša, E. Žagar, D. Pahovnik Eur. Polym. J. 2024, 204, 112707.

5- A. Kočman, D. Pahovnik, E. Žagar, P. Utroša Angew. Chem. Int. Ed. 2026, 65, e21891.

Acknowledgments

All the authors acknowledge financial support from the Slovenian Research and Innovation Agency - Research Core Funding P2-0145 and projects J2-9214, N2-0131, J2-4438 and Z2-4439.