Facile Synthesis of Non‐Proteinogenic Sulfur‐Containing Cyclic Dipeptides and Their Structure–Antioxidant Activity Relationship

Cyclic peptides are peptidic macrocycles with ring‐constrained backbones that have distinct physicochemical and biological properties, with the simplest being cyclic dipeptides. Four cyclic dipeptides, cyclo(Pro‐Pro), cyclo(Pip‐Pip), cyclo(PrS‐PrS), and the unique sulfur‐rich cyclo(PipS‐PipS), were synthesized from unprotected amino acids by using a one‐pot thionyl chloride‐mediated cyclization process, producing 19%–40% without the use of protective‐group strategies. FTIR, NMR, and high‐resolution mass spectrometry (HRMS) were used to confirm the structures. The 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging assay was used to assess antioxidant activity, and it was discovered that sulfur incorporation and six‐membered ring size significantly increase radical quenching. A cloud‐based platform was used to predict electronic properties, such as HOMO‐LUMO gaps, dipole moments, and oxidation potential. Compounds with smaller HOMO‐LUMO gaps and lower oxidation potentials had higher DPPH scavenging efficiencies, establishing a clear structure‐property‐activity relationship. This study identifies promising sulfur‐containing cyclic dipeptides for future development as antioxidant therapeutics and presents a scalable pathway to diverse cyclic dipeptides.