Connectivity Inversion Tunes Glycosyl Imidate Reactivity: N ‐(Trifluoromethyl)benzimidates for Catalytic and One‐Pot Glycosylation

Comprehensive Summary

Glycosylation is a fundamental transformation in carbohydrate chemistry that is central to the synthesis of oligosaccharides and glycoconjugates. Glycosyl imidates are widely used glycosyl donors that enable catalytic activation; however, balancing their stability and reactivity remains an ongoing challenge. In this work, we introduce glycosyl N ‐(trifluoromethyl)benzimidates (TFBs) as a new family of glycosyl donors through a connectivity inversion strategy from conventional N ‐phenyl trifluoroacetimidates (PTFAs). TFB donors can be readily prepared from commercially available phenylacetonitrile, leaving space for future optimization. Comprehensive evaluation of TFB donors demonstrates their broad applicability in catalytic glycosylations. These donors are compatible with diverse glycosyl acceptors and challenging substrate classes, including glucuronate and ketosyl donors, and N ‐nucleophiles. Compared with PTFAs, TFB donors exhibit improved spectral resolution and their favorable leaving‐group properties simplify purification procedures. Importantly, TFB donors display enhanced stability while maintaining sufficient glycosylation activity. Computational studies reveal that the reduced reactivity originates from an increased activation barrier during TMSOTf‐mediated donor activation, providing mechanistic insights into how imidate connectivity influences glycosyl donor behavior. The differentiated reactivity profiles of TFB and PTFA donors enable orthogonal one‐pot assembly of oligosaccharides through controlled promoter activation, and enhance chemo‐selective one‐pot synthesis. Overall, this study establishes connectivity inversion as a useful strategy for tuning glycosyl imidate reactivity and provides a new platform for developing stable yet effective glycosyl donors for streamlined carbohydrate synthesis.