Ahirwar, Saurabh Kumar2026-10-082026-10-08https://hdl.handle.net/1885/733816102Late-stage peptide backbone modifications using electrochemistry are an underexplored area in peptide chemistry. The peptide backbone has been reported to influence solubility, aggregation and folding patterns and hence a new, green and economically viable method to incorporating backbone modifications would be a valuable addition to the suite of available tools for peptide synthesis. In this thesis, we repurpose two existing peptide backbone-protecting groups as electroauxiliaries that are compatible with general Fmoc-solid-phase peptide synthesis (SPPS) conditions. These auxiliaries enable a new pathway for diverse and orthogonal late-stage backbone modifications under mild conditions. In this work: Chapter 1 provides a general introduction, covering existing methods for chemical and electrochemical modifications of peptides. The literature on peptide-modifying electroauxiliaries is discussed in detail, along with the importance of macrocyclisation and bioconjugation. Chapter 2 introduces two benzylic backbone protecting groups, and their electrochemical activity was evaluated by mounting them on small dipeptides and examining their redox-behaviour using cyclic voltammetry. Once electroactivity was established, SPPS-compatible, Fmoc-protected amino acids were synthesised to introduce the electroauxiliaries into larger peptides. Chapter 3 investigates the reactivity of the backbone electroauxiliaries in more detail using hydrophobic pentapeptides. Both the electroauxiliaries were installed into model peptides and conditions for their anodic methoxylation to forge peptide N,O-acetals were optimised. The optimal conditions were then used to screen the effects of different functional groups (amino acid screening) on the anodic oxidation. Several nucleophilic alcohols were used as co-solvents to generate a library of functionalized N,O-acetals. These intermediates were then subjected to further chemical modifications to enable facile, permanent modifications at the peptide backbone. The functionalities on N,O-acetals were further leveraged for bioconjugation and macrocyclisation reactions. Chapter 4 presents preliminary results on the design and incorporation of a new electroauxiliary and its influence on the electrochemical activity of the pentapeptide model. This chapter also discusses the unique reactivity of sulfur in the context of electrochemical modifications of peptides. Chapter 5 summarises the electrochemical strategies developed for late-stage peptide backbone modifications. The chapter also outlines future directions for exploring the use of these electroauxiliaries as turn-inducers and for extending the methodology to larger peptides and proteins. Finally, chapter 6 presents all experimental details and characterisation data for the products described in chapters 2, 3, and 4.en-AU202610.25911/Z19A-YQ63