Cycloadditions of Trans‐Cyclooctenes and Nitrones as Tools for Bioorthogonal Labelling

Abstract

Trans‐cyclooctenes (TCOs) represent interesting and highly reactive dipolarophiles for organic transformations including bioorthogonal chemistry. Herein we show that TCOs react rapidly with nitrones and that these reactions are bioorthogonal. Kinetic analysis of acyclic and cyclic nitrones with strained‐trans‐cyclooctene (s‐TCO) shows fast reactivity and demonstrates the utility of this cycloaddition reaction for bioorthogonal labelling. Labelling of the bacterial peptidoglycan layer with unnatural d‐amino acids tagged with nitrones and s‐TCO‐Alexa488 is demonstrated. These new findings expand the bioorthogonal toolbox, and allow TCO reagents to be used in bioorthogonal applications beyond tetrazine ligations for the first time and open up new avenues for bioorthogonal ligations with diverse nitrone reactants.

Environmental Effect of Potential Radiopharmaceuticals Residuals

“…The dataset consists of 11 molecules -tetrazine derivatives and 12 moleculescyclooctene derivatives (see supplementary Table A1). All of these bifunctional moieties are non-radioactive parts of modern radiopharmaceuticals responsible for pharmacokinetics and conjugation, able to provide click reaction between each other and bio conjugate through oxime, hydrazone or peptide bonding [33,34]. In the set molecule from C1 to C15 are newly synthesized and the rest are commercially available (see supplementary Table A1).…”

Predicting reactivity for bioorthogonal cycloadditions involving nitrones

“…Rate constants were measured previously. 17,23,42,43 of 21.4-23.0 kcal mol À1 , and 1b gave the smallest value. Distortion energy of nitrones also had the smallest value for 1b, suggesting that 1b had the least steric hindrance (entry 2).…”

“…These include strain-promoted alkynenitrone cycloadditions (SPANC) as well as trans-cyclooctenenitrone ligations that occur selectively and with high reaction velocities. [15][16][17][18][19][20][21][22][23] Furthermore, nitrones provide an added level of versatility in that their reactivity can be tuned stereoelectronically, through substituent effects on both the nitrone nitrogen atom and on the adjacent carbon atoms. This tuneability has enabled duplex labelling experiments with different nitronealkyne pairs.…”

“…Recently we have reported that nitrones will react with different trans-cyclooctenes (TCO) in TCO-nitrone ligation reactions. 23 While these reactions are somewhat slower than their tetrazine counterparts, they still represent useful chemical transformations with utility in bioorthogonal applications and give other applications to TCOs when tetrazine reactions are not possible. Here our analyses show that strained TCO (s-TCO) has little requirement for distortion prior to reaching the transition state with nitrone reaction partners and that nitrone reaction partners also do not need to achieve signicant distortion in the Table 1.…”

“…To compare calculated energies with experimental data, we used rate constant data previously measured for entries where numbers were available. 17,23,42,43 Since rate constants are related to reaction barriers through transition state theory, we plotted the negative log of the bimolecular rate constants versus calculated parameters. Importantly, distortion energies calculated for nitrones and dipolarophiles do not readily predict the trend in reactivities that we observe experimentally.…”