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Synthesis of Carbohydrate-Functionalised Sequence-Defined Oligo(amidoamine)s by Photochemical Thiol[BOND]Ene Coupling in a Continuous Flow Reactor

Authors

  • Felix Wojcik,

    1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
    2. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
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    • These authors contributed equally to this work.

  • Dr. Alexander G. O'Brien,

    1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
    2. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
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    • These authors contributed equally to this work.

  • Sebastian Götze,

    1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
    2. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
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  • Prof. Dr. Peter H. Seeberger,

    Corresponding author
    1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
    2. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
    • Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
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  • Dr. Laura Hartmann

    Corresponding author
    1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
    2. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
    • Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
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Abstract

Poly/oligo(amidoamine)s (PAAs) have recently been recognised for their potential as well-defined scaffolds for multiple carbohydrate presentation and as multivalent ligands. Herein, we report two complimentary strategies for the preparation of such sequence-defined carbohydrate-functionalised PAAs that use photochemical thiol[BOND]ene coupling (TEC) as an alternative to the established azide–alkyne cycloaddition (“click”) reaction. In the first approach, PAAs that contained multiple olefins were synthesised on a solid support from a new building block and subsequent conjugation with unprotected thio-carbohydrates. Alternatively, a pre-functionalised building block was prepared by using TEC and assembled on a solid support to provide a carbohydrate-functionalised PAA. Both methods rely on the use of a continuous flow photoreactor for the TEC reactions. This system is highly efficient, owing to its short path length, and requires no additional radical initiator. Performing the reactions at 254 nm in Teflon AF-2400 tubing provides a highly efficient TEC procedure for carbohydrate conjugation, as demonstrated in the reactions of O-allyl glycosides with thiols. This method allowed the complete functionalisation of all of the reactive sites on the PAA backbone in a single step, thereby obtaining a defined homogeneous sequence. Furthermore, reaction at 366 nm in FEP tubing in the flow reactor enabled the large-scale synthesis of an fluorenylmethyloxycarbonyl (Fmoc)-protected glycosylated building block, which was shown to be suitable for solid-phase synthesis and will also allow heterogeneous sequence control of different carbohydrates along the oligomeric backbone. These developments enable the synthesis of sequence-defined carbohydrate-functionalised PAAs with potential biological applications.

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