Optimization and Scale-up of a Peptide-Based Ser-Ser Dimethacrylate Zwitterionic Cross-Linker for Nonfouling Polyampholytes

Zwitterionic cross-linkers, when integrated into polyampholytes, create continuous networks of charge density that enhance nonfouling performance via tightly bound ionic solvation layers─outperforming their uncharged counterparts regarding biocompatibility while retaining tunable physical characteristics. Despite their potential in biomedical and environmental applications, zwitterionic cross-linkers remain underexplored. Given that amino acids exhibit intrinsic zwitterionic behavior at physiological pH, peptide-based cross-linkers present a compelling avenue for innovation. In this work, we report the multigram-scale synthesis of serine-serine dimethacrylate (Ser-Ser), an emerging dipeptide-based zwitterionic cross-linker. Multiple synthetic strategies were evaluated, ultimately converging on a streamlined six-step route requiring only three chromatographic purifications. This scalable and efficient synthesis paves the way for a broader investigation and application of peptide-derived zwitterionic cross-linkers in the design of advanced, biocompatible polymeric materials.