Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles. Issue 27 (6th June 2019)

• Record Type: Journal Article
• Authors: Tu, Julian; Svatunek, Dennis; Parvez, Saba; Liu, Albert C.; Levandowski, Brian J.; Eckvahl, Hannah J.; Peterson, Randall T.; Houk, Kendall N.; Franzini, Raphael M.
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 27(2019)
• Page Start: 9043
• Page End: 9048
• Publication Date: 2019-06-06
• Subjects: bioconjugation -- bioorthogonal chemistry -- chemoselectivity -- cycloadditions -- dispersion forces; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201903877
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Now it is shown that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure–activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 L mol −1 s −1 were accessible by combining bulky and electron‐withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles. Abstract : Rise of bulky tetrazines : Highly stable tetrazines that react rapidly with isonitriles are presented. Bulky tetrazine substituents sterically attract the isocyano group in the cycloaddition transition state and block the approach of strained alkenes. These characteristics enable rapid bioorthogonal labeling and release reactions and allow for triple‐orthogonal protein labeling.