Enhanced Selectivity of Chalcogen Bonding over Halogen Bonding Catalyzed <i>C</i> ‐glycosylation Through Differentiated Intermediate Activation

σ-hole-based noncovalent interactions are gaining intense attention as robust tools in stereoselective carbohydrate synthesis. However, the mechanistic understanding behind the differing performance between chalcogen bonding (ChB) catalysis versus halogen bonding (XB) catalysis in chemical glycosylations still remains unresolved. Herein, we disclose a remarkable instance whereby phosphonochalcogenide (PCH) catalysis displays pronounced selectivity and reactivity elevation in aryl-C-glycosylations compared to XB catalysis. Mechanistic studies revealed that the enhanced stereocontrol can be attributed to the differentiated downstream activation of a key bicyclic intermediate. Hammett analysis supported that ChB catalysis shifted the C-glycosylation toward the S_N1 domain, while the XB catalysis proceeded with S_N2 characteristics. DFT calculations further illuminated that the downstream ChB catalytic engagement involved all four selenium σ-holes engaging in two bifurcated ChB modes. This study thus sheds new light that the selectivity benefits of ChB catalysis could be accounted for by privileged mechanistic access into an otherwise inaccessible stereoselective pathway.