Increasing Tetrazine Reactivity in the IEDDA Reaction
Hannes Mikula shows that the N-acylation of 3-aminotetrazines leads to increased reactivity in bioorthogonal ligations.
Acylation-Mediated ‘Kinetic Turn-On’ of 3-Amino-1,2,4,5-tetrazines: S. Kronister, D. Svatunek, C. Denk, H. Mikula
Synlett 2018, DOI: 10.1055/s-0036-1591764
Strain-induced ‘click chemistry’, such as the Inverse Electron Demand Diels–Alder (IEDDA) reaction, between cyclooctynes or trans-cyclooctenes and tetrazines, is emerging as a powerful technology for in vivo applications in targeted therapy and imaging. A full understanding of the structural and kinetic parameters for maximizing the efficiency and rate of the process is highly desirable but not yet entirely achieved. Recently, the group of Dr. Hannes Mikula at TU Wien (Vienna, Austria) reported an important step forward toward that goal.
Dr. Mikula said: “Low-molecular-weight 3-aminotetrazines are useful bioorthogonal reagents and can be used as ‘click tags’ that – upon N-acylation – show an increased reactivity in inverse electron demand Diels–Alder reactions of up to 700-fold.
Herein, we show that N-acylation of 3-aminotetrazines leads to an increased reactivity in bioorthogonal ligations of up to 740-fold, which is key for the development of labeling strategies wherein the tetrazine reagent does not necessarily need to be removed prior to the subsequent click reaction as the N-acylated intermediate is significantly more reactive.