Carbene-catalyzed site-selective sulfonylation and modular edition of monosaccharides for hydroxyl group stereoinversion and swapping

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Abstract
Monosaccharides are ubiquitous motifs in natural and synthetic molecules, yet methods for their selective structure editing remain limited due to the multiple hydroxy groups for differentiation and their structural complexity. Among possible strategies for stereoinversion and functional group swapping of saccharides, the classical SN2 substitution of alcohols via sulfonate esters offers a potentially robust approach. A central challenge, however, is the selective functionalization of sulfonyl groups on specific hydroxyl moiety. Here we report an organocatalytic approach to enable site-selective sulfonylation of minimally protected saccharides by exploiting an underexplored N-heterocyclic carbene (NHC)-derived sulfonyl-azolium intermediate. Distinct NHC scaffolds govern regioselectivity for the sulfonyl group transfer, overcoming the challenge of differentiating multiple hydroxyl units in complex sugar substrates. The installed sulfonates serve as versatile leaving groups for subsequent nucleophilic substitution, constituting a "sulfonylation-swapping" strategy that transforms abundant sugars into diverse high-value rare sugars, including pharmaceutically relevant structures such as dapagliflozin analogues. Furthermore, the readily accessed rare sugars exhibit intriguing antimicrobial activity against various plant pathogens, demonstrating significant potential for the development of potent fungicide agents.

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