γ-Functional Iminiumthiolactones for Single or Double Modification of Peptides

Thiolactones have been extensively studied as efficient ligation strategy, yet, their reactivity towards bio-based building blocks remains limited. In this manuscript, we present their more reactive successors, iminiumthiolactones (ITL), which show superior reactivity towards amine-containing substrates. Based on the Traut’s reagent we synthesized several ITLs from glycidol precursors and investigated several orthogonal modification reactions. After performing basic calculations on our substrates to substantiate their predicted reactivity, we picked one of our derivatives (γ-allyl functional ITL 3b) to study model reactions and explore the orthogonality of its different reaction pathways. As a more challenging substrate, we further choose Lysozyme C to be modified with our γ-allyl ITL (3b) using low reactant concentrations (1 mM or 50 μM), near-neutral pH (7.4 or 8.0) and stoichiometric reactant ratios. Under the studied conditions, we successfully demonstrate that our ITL derivative exhibits orthogonal and enhanced reactivity in a single or double modification towards biological substrates. As such, we believe that γ-functional ITLs may open up promising opportunities to incorporate biological building blocks into existing functional molecules, polymeric frameworks and materials.