Total Synthesis of Conjugation-Ready Sulfated Red Algae Carrageenan Oligosaccharides for Sensing Applications

Carrageenans are versatile sulfated marine galactans that possess attractive modification-dependent bulk properties, making them prime candidates for various cosmetic, drug delivery, and food-related applications. The structural diversity and intrinsic complexity of carrageenans hamper access to homogeneous polysaccharides, limiting the development of many carrageenan-based applications. We devised a synthetic strategy for the acquisition of a panel of γ-carrageenan-derived oligosaccharides with varying sulfation profiles and chain length. To that end, we synthesized a set of specialized building blocks with an elaborate multilevel protecting group hierarchy, tailor-made to specifically accommodate the structural complexity of carrageenans. In doing so, we uncovered interdependent protecting group and reactivity constraints, which we resolved strategically to adapt the synthetic route across the panel of carrageenans and minimize trade-offs. Assembly of di-, tri-, and tetrasaccharides with precise control over monomer connectivity and regiodefined sulfation on a conjugation-ready linker showcased the first total synthesis of homogeneous carrageenan oligogalactans. We demonstrated that the application of the curated panel enabled elucidation of the effect of γ-carrageenan molecular features on IL-8 binding preferences via electrochemical sensing and surface analyses.