Facile Solid Phase Synthesis of YEE(ah-GalNAc)3, a Ligand with Known High Affinity for the Asialoglycoprotein Receptor

A simple cluster glycoside, containing three residues of N-acetylgalactosamine with proper inter-residual distances, can be a high-affinity ligand for the asialoglycoprotein receptor (ASGPr) of mammalian liver. Tris(GalNAc-aminohexyl)glycoside of tyrosyl(glutamyl)glutamate YEE(ah-GalNAc)3 1, which is known to have sub-nanomolar affinity for the asialoglycoprotein receptor, was efficiently synthesized by using succinic acid as a linker to anchor GalNAc-aminohexyl glycoside to solid phase resin, followed by coupling the building blocks of Fmoc-(ah-α-GalNAcAc3)Glu and Fmoc-Tyr-OH to obtain YEE(ah-GalNAc)3 with a total yield of 83%.