N‐Glycosyl Triazoline Glycomimetics via Huisgen Cycloaddition With an Electron‐Deficient Alkene and BF 3 ‐Catalysed Triazoline Fragmentation to Aziridines

Triazoline and aziridine derivatives were synthesised by diastereo‐ and regioselective Huisgen cycloaddition of 2,3,4,6‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl azide with ethyl 4,4,4‐trifluorocrotonate. Use of a continuous‐flow reactor led to reduced reaction time and enabled use of ethyl acetate as a greener solvent for the cycloaddition. Thermolysis of trans‐ triazolines yielded trans‐ aziridines, while treatment with BF 3 ·OEt 2 (or BnOTf) produced cis‐ aziridines. Density functional theory calculations supported a mechanism for trans‐ triazoline conversion to cis‐ aziridine involving boron trifluoride catalysed NN bond cleavage to give an intermediate with boron trifluoride stabilised nitrogen that then undergoes S N 2 reaction. Deacetylation yielded N ‐galactopyranosyl aziridines and triazolines, which were identified as substrate‐based inhibitors of β‐galactosidase. Synthesis of glycosyl aziridines from reactions of N ‐phenylmaleimide is included.