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Click‐to‐Release from trans ‐Cyclooctenes: Mechanistic Insights and Expansion of Scope from Established Carbamate to Remarkable Ether Cleavage
Author(s) -
Versteegen Ron M.,
ten Hoeve Wolter,
Rossin Raffaella,
de Geus Mark A. R.,
Janssen Henk M.,
Robillard Marc S.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201800402
Subject(s) - bioorthogonal chemistry , chemistry , cleavage (geology) , carbamate , tyrosine , ether , vinyl ether , combinatorial chemistry , linker , tautomer , amine gas treating , cleave , click chemistry , organic chemistry , biochemistry , enzyme , geotechnical engineering , fracture (geology) , computer science , engineering , copolymer , operating system , polymer
Abstract The bioorthogonal cleavage of allylic carbamates from trans ‐cyclooctene (TCO) upon reaction with tetrazine is widely used to release amines. We disclose herein that this reaction can also cleave TCO esters, carbonates, and surprisingly, ethers. Mechanistic studies demonstrated that the elimination is mainly governed by the formation of the rapidly eliminating 1,4‐dihydropyridazine tautomer, and less by the nature of the leaving group. In contrast to the widely used p ‐aminobenzyloxy linker, which affords cleavage of aromatic but not of aliphatic ethers, the aromatic, benzylic, and aliphatic TCO ethers were cleaved as efficiently as the carbamate, carbonate, and esters. Bioorthogonal ether release was demonstrated by the rapid uncaging of TCO‐masked tyrosine in serum, followed by oxidation by tyrosinase. Finally, tyrosine uncaging was used to chemically control cell growth in tyrosine‐free medium.