Total Synthesis of the SJG-2 Glycan: General Strategies for Constructing Sterically Congested Sialylated Glycans

Gangliosides are a diverse class of glycosphingolipids whose sialylated glycans regulate processes ranging from neuronal repair to immune responses. Among them, SJG-2, an echinoderm-derived ganglioside with potent neuroregenerative activity, stands out for its rare and highly branched trisialylated glycan motif. The unusual architecture of the heptasaccharide SJG-2 glycan with two terminal sialic acids attached to galactose (Gal) via α(2,3)- and α(2,4)-sialylations and an additional internal β(1,8)-sialylation to another sialic acid has rendered it synthetically inaccessible for over two decades. Here, we report the first total synthesis of the SJG-2 glycan. A conformational inversion strategy using a ¹C₄-configured Gal acceptor enabled efficient α(2,4)- and α(2,3)-sialylations. In the key convergent [4 + 3] glycosylation, selective <i>N</i>-acetyl,5-<i>N</i>,4-O-carbonyl protection of sialic acid suppressed competing C8 reactivity, while subsequent deacetylation proved essential for forming the β(1,8)-glycosidic bond. This work achieves a long-standing synthetic goal and establishes broadly applicable strategies for constructing sterically congested sialylated glycans, opening new opportunities to access complex gangliosides and explore their neurobiological functions.