Stable amide activation of N-acetylated glycosamines for the synthesis of fused polycyclic glycomimetics

Abstract

N-Acetylation of carbohydrates is an underexplored target for chemoselective derivatization and generation of glycomimetic scaffolds. Through mild amide activation, we report that N-acetimidoyl heterocycles are stable in neutral or basic conditions yet are excellent leaving groups through acid catalysis. While this specific reactivity could prove broadly useful in amide activation strategies, stably activated N-acetylated sugars can also be diversified using libraries of hydrazides. We optimized an acid-catalyzed one-pot sequence that includes nucleophilic displacement, cyclodehydration, and intramolecular glycosylation to ultimately deliver pyranosides fused to morpholines or piperazines. This strategy of stable activation followed by acid-triggered reaction sequences exemplifies the efficient assembly of 3D-rich fused glycomimetic libraries.