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

    17 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

    Fingerprint

    Cyclooctanes
    Ethers
    Carbamates
    Ether
    Tyrosine
    Carbonates
    Esters
    Monophenol Monooxygenase
    Cell growth
    Amines
    Oxidation

    Keywords

    • cleavage reactions
    • click chemistry
    • pyridazine elimination
    • tetrazines
    • trans-cyclooctene

    Cite this

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    title = "Click-to-release from trans-cyclooctenes: mechanistic insights and expansion of scope from established carbamate to remarkable ether cleavage",
    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.",
    keywords = "cleavage reactions, click chemistry, pyridazine elimination, tetrazines, trans-cyclooctene",
    author = "Versteegen, {Ron M.} and {ten Hoeve}, Wolter and Raffaella Rossin and {de Geus}, {Mark A.R.} and Janssen, {Henk M.} and Robillard, {Marc S.}",
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    Click-to-release from trans-cyclooctenes : mechanistic insights and expansion of scope from established carbamate to remarkable ether cleavage. / Versteegen, Ron M.; ten Hoeve, Wolter; Rossin, Raffaella; de Geus, Mark A.R.; Janssen, Henk M.; Robillard, Marc S. (Corresponding author).

    In: Angewandte Chemie - International Edition, Vol. 57, No. 33, 13.08.2018, p. 10494-10499.

    Research output: Contribution to journalArticleAcademicpeer-review

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    AU - Versteegen, Ron M.

    AU - ten Hoeve, Wolter

    AU - Rossin, Raffaella

    AU - de Geus, Mark A.R.

    AU - Janssen, Henk M.

    AU - Robillard, Marc S.

    PY - 2018/8/13

    Y1 - 2018/8/13

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