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 .