γ-Functional Iminiumthiolactones for the Single and Double Modification of Peptides

Thiolactones (TL) can be readily incorporated into polymeric materials and have been extensively used as a ligation strategy despite their limited reactivity toward amine-containing substrates. Comparatively, iminiumthiolactones (ITL) are much more reactive, yet to this day, only the nonsubstituted ITL known as Traut's reagent is commercially available and used. In this work, we advance current TL/ITL chemistry by introducing reactive side groups to the ITL heterocycle in the γ-position, which can be orthogonally modified without affecting the ITL heterocycle itself. To study the reactivity of γ-functional ITLs, we subject one of our derivatives (γ-allyl-functional ITL 3b) to model reactions with several peptides and a chosen protein (lysozyme C). Using mild reaction conditions, we successfully demonstrate that the γ-functional ITL exhibits orthogonal and enhanced reactivity in a single or double modification while introducing a new functional handle to the biological substrate. We believe that γ-functional ITLs will advance the original Traut chemistry and open promising opportunities for the bioconjugation of biological building blocks to existing functional molecules, polymers, and materials.