An Exploration of Vinamidinium Salts for Frame‐Shifted Synthesis

Oligoheterocycles are widely used in drug discovery and materials science, where they serve as attractive alternatives to peptide fragments. There is strong interest in understanding the structural correspondence between heterocycles and amino acid motifs to recapitulate key binding elements while improving metabolic stability. A frame‐shifted synthetic strategy was recently introduced in which iterative heterocycle formation replaced the assembly of prefabricated units, enabling concise access to oligoheterocycles from simple feedstock‐derived building blocks. Here, this approach is extended to novel vinamidinium salts for chemodivergent assembly of versatile peptide–heterocycle hybrids. This work includes the design and analysis of new vinamidinium reagents and demonstrates their utility in the efficient incorporation of β‐amino acid–mimicking heterocyclic inserts into peptide frameworks.