Solid-phase peptide synthesis (SPPS) has revolutionised our ability to access peptides as biological tools, new therapies, and novel materials. However, methods that allow direct, late-stage peptide modifications with concomitant resin cleavage are currently limited. In 1982, Wasserman and Lu reported a unique method for the formation of peptide bonds via the regioselective nucleophilic acyl substitution of triamide intermediates with canonical unprotected amino acids.1 The triamide intermediates were accessible in situ from the photooxidation of 2,4,5-trisubstituted oxazoles derived from simple N-protected amino acids.1-3 The present work aims to harness the reactivity of in situ generated triamides to facilitate the direct modification of peptides on the solid-phase.
This presentation will detail our studies toward the design and synthesis of a resin linker incorporating the 2,4,5-trisubstituted oxazole moiety. The linker permits photooxidation and subsequent on-resin triamide formation, thus allowing simultaneous peptide cleavage and C-terminal functionalisation via nucleophilic acyl substitution. Optimal photooxidation reaction conditions have been defined using a model system through the screening of photosensitisers, light sources, and catalyst loadings. A range of nucleophiles and protecting groups have also been probed through model reactions to evaluate the compatibility of the photooxidation with diverse amino acid side chains. Remarkably, triamide formation proceeds smoothly under mild, ambient photooxidation conditions and leads to regioselective nucleophilic substitution. Resin cleavage via nucleophilic attack unlocks multiple avenues for more efficient and selective late-stage peptide modifications including macrocyclisation, thioester formation, and peptide fragment condensation in a way that was previously inaccessible using conventional SPPS. This method therefore has the potential to expedite access to a vast library of new synthetic peptides, including promising therapeutic leads.