Synthesis of a New Series of Sialylated Homo‐ and Heterovalent Glycoclusters by using Orthogonal Ligations

The synthesis of heteroglycoclusters (hGCs) is being subjected to rising interest, owing to their potential applications in glycobiology. In this paper, we report an efficient and straightforward convergent protocol based on orthogonal chemoselective ligations to prepare structurally well‐defined cyclopeptide‐based homo‐ and heterovalent glycoconjugates displaying 5‐N‐acetyl‐neuraminic acid (Neu5Ac), galactose (Gal), and/or N‐acetyl glucosamine (GlcNAc). We first used copper‐catalyzed azide–alkyne cycloaddition and/or thiol‐ene coupling to conjugate propargylated α‐sialic acid 3, β‐GlcNAc thiol 5, and β‐Gal thiol 6 onto cyclopeptide scaffolds 7–9 to prepare tetravalent homoglycoclusters (10–12) and hGCs (13–14) with 2:2 combinations of sugars. In addition, we have demonstrated that 1,2‐diethoxycyclobutene‐3,4‐dione can be used as a bivalent linker to prepare various octavalent hGCs (16, 19, and 20) in a controlled manner from these tetravalent structures. Extending molecular diversity: A straightforward convergent protocol based on orthogonal chemoselective ligations is described to generate heteromultivalency in a controlled manner. Copper‐catalyzed azide–alkyne cycloaddition (CuAAC) and thiol‐ene coupling (TEC) are first used to functionalize cyclopeptide scaffolds with propargyl and thiol glycosides to generate tetravalent heteroglycoclusters with 2:2 combinations of sugars. In addition, these compounds can be easily (hetero)dimerized by pH‐dependent sequential coupling with diethyl squarate to afford various octavalent structures.