Strained bonds1 provide unique opportunities for the construction of complex molecules, the design of new therapies and the preparation of high-value materials. Targeted release of the potential energy locked in high energy molecular constructs provides a particularly appealing approach to the chemoselective modification of complex biomolecules. Indeed, concepts such as ring strain—perhaps best exemplified in the application of cyclooctynes in strain-promoted [3 + 2] cycloadditions2—have become hallmarks of modern bioorthogonal chemistry.
This talk will focus on harnessing molecular strain for further application in the direct modification of native amino acids and peptides.3 The rapid synthesis of a valuable toolbox of highly-strained electrophiles featuring the bicyclobutane motif will be detailed, and the utility of these compounds for the strain-release functionalization of proteinogenic nucleophiles will be critically examined. A particular focus on the application of bifunctional electrophiles for the dual modification of peptides on-resin and in solution will reveal the potential of this novel reagent class for residue-specific bioconjugation and peptide cyclization.