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

• Published in: Chembiochem : a European journal of chemical biology Vol. 21; no. 7; pp. 948 - 951
• Main Authors: Margison, Kaitlyn D., Bilodeau, Didier A., Mahmoudi, Farnaz, Pezacki, John Paul
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.04.2020
• Subjects: Amino acids; bioconjugation; bioorthogonal chemistry; Cycloaddition; Cycloaddition Reaction; Cyclooctanes - chemistry; Hydrazines - chemistry; Isomerism; Kinetics; Labeling; Nitrogen Oxides - chemistry; nitrones; Peptidoglycan - chemistry; peptidoglycan labeling; Peptidoglycans; Reagents; trans-cyclooctene; trans-cyclooctene; bioconjugation; bioorthogonal chemistry; nitrones; peptidoglycan labeling
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201900627

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. Expanding the bioorthogonal toolbox: Reaction development and kinetic analysis of the cycloaddition between nitrones and trans‐cyclooctenes (TCOs) demonstrates the utility of this reaction for bioorthogonal labelling. By using TCOs and nitrones as reagents, robust labelling of the bacterial peptidoglycan layer is achieved, thus demonstrating this reaction as a new bioorthogonal ligation tool.