Click-to-release from trans-cyclooctenes: mechanistic insights and expansion of scope from established carbamate to remarkable ether cleavage

Ron M. Versteegen, Wolter ten Hoeve, Raffaella Rossin, Mark A.R. de Geus, Henk M. Janssen, Marc S. Robillard (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10494-10499
Number of pages6
JournalAngewandte Chemie - International Edition
Volume57
Issue number33
DOIs
Publication statusPublished - 13 Aug 2018

Keywords

  • cleavage reactions
  • click chemistry
  • pyridazine elimination
  • tetrazines
  • trans-cyclooctene
  • Ethers/chemistry
  • Tetrazoles/chemistry
  • Carbamates/chemistry
  • Oxidation-Reduction
  • Click Chemistry
  • Humans
  • Cyclooctanes/chemistry
  • Cycloaddition Reaction
  • Isomerism
  • Tyrosine/blood
  • Monophenol Monooxygenase/chemistry
  • Amines/chemistry
  • Cell Line, Tumor

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