Hexafluoroisopropanol-Promoted Stereospecific Glycosylation Enables Efficient Access to N−O-Linked 1,2- <i>cis</i> -2-Amino Glycosides

High Resolution Image Download MS PowerPoint Slide 1,2- cis -2-Amino glycosidic linkages are prevalent in biologically important molecules; however, they are difficult to form reliably in high stereoselectivity. Herein, we disclose a catalyst-free, α-stereospecific oxime O -glycosylation in hexafluoroisopropanol (HFIP) that assembles diverse N−O-linked 2-nitro-α-glycosides (60 examples), enabling facile access to 1,2- cis -2-amino glycoside mimetics. The synthetic utility of this approach is highlighted by the late-stage functionalization of complex molecules and various synthetic transformations. Nuclear magnetic resonance (NMR) studies reveal strong hydrogen-bonding (HB) interactions between HFIP and 2-nitroglycals/oximes. Computational studies reveal a novel glycosylation mechanism in which aggregated HFIP trimers play a critical role in facilitating HB activation of substrates and then enable the α-stereospecific, concerted 1,4-addition of oxime to 2-nitroglycal and protonation through a proton shuttle-mediated macrocyclic transition state. Overall, this work uncovers the HFIP trimer as an efficient hydrogen-bond catalyst for stereoselective glycosylation, providing a powerful tool for α-stereospecific synthesis of N−O-linked 1,2- cis -2-amino glycosides.