Divalent Triazole-Linked Carbohydrate Mimetics: Synthesis by Click Chemistry and Evaluation as Selectin Ligands

Abstract

Starting from an enantiopure 3-amino-substituted pyran derivative, the synthesis of a series of divalent 1,2,3-triazole-linked carbohydrate mimetics is described. The preparation of the required 3-azido-substituted pyran proceeds smoothly by copper-catalyzed diazo transfer. Using different conditions for the Huisgen-Meldal-Sharpless cycloaddition, this azide reacts with several diynes to furnish the desired divalent carbohydrate mimetics bearing rigid or flexible linker units. The in situ generation of the 3-azidopyran in the presence of Cu/C as catalyst followed by the reaction with the alkyne allows a direct one-pot transformation from the 3-aminopyran to the desired click products. We also examined the Sakai-Westermann method that transfers primary amines with the aid of α,α-dichlorotosylhydrazones into 1,2,3-triazoles. These copper-free click conditions were applied for the first time to the preparation of a divalent compound. The O-sulfation of the carbohydrate mimetics was achieved using the SO3-DMF complex under careful 1H-NMR control. Five polysulfated compounds could be obtained in pure form and these were tested by surface plasmon resonance spectroscopy as inhibitors of L-selectin giving IC50 values between 45 nm and 50 µm.