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Bridge‐Clamp Bis(tetrazine)s with [N] 8 π‐Stacking Interactions and Azido‐ s ‐Aryl Tetrazines: Two Classes of Doubly Clickable Tetrazines
Author(s) -
Mboyi Clève D.,
Vivier Delphine,
Daher Ahmad,
FleuratLessard Paul,
Cattey Hélène,
Devillers Charles H.,
Bernhard Claire,
Denat Franck,
Roger Julien,
Hierso JeanCyrille
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201911947
Subject(s) - tetrazine , bioorthogonal chemistry , cycloaddition , bioconjugation , click chemistry , chemistry , combinatorial chemistry , aryl , stacking , organic chemistry , catalysis , alkyl
Click chemistry at a tetrazine core is useful for bioorthogonal labeling and crosslinking. Introduced here are two new classes of doubly clickable s ‐aryl tetrazines synthesized by Cu‐catalyzed cross‐coupling. Homocoupling of o ‐brominated s ‐aryl tetrazines leads to bis(tetrazine)s structurally characterized by tetrazine cores arranged face‐to‐face. [N] 8 π‐stacking interactions are essential to the conformation. Upon inverse electron demand Diels–Alder (iEDDA) cycloaddition, the bis(tetrazine)s produce a unique staple structure. The o ‐azidation of s ‐aryl tetrazines introduces a second proximal intermolecular clickable function that leads to double click chemistry opportunities. The stepwise introduction of fluorophores and then iEDDA cycloaddition, including bioconjugation to antibodies, was achieved on this class of tetrazines. This method extends to (thio)etherification, phosphination, trifluoromethylation and the introduction of various bioactive nitrogen‐based heterocycles.