Pd‐Catalyzed Stereospecific and Ligand‐Controlled Regiodivergent Suzuki–Miyaura Cross‐Coupling for the Synthesis of 3‐<i>C</i>‐Glycals and 2,3‐Unsaturated <i>C</i>‐Glycosides

Abstract The selective modification of carbohydrates to achieve structural complexity has emerged as a crucial strategy in carbohydrate‐based drug development. However, the intricate stereochemistry and densely packed functional groups of carbohydrates pose significant challenges for precise stereoselectivity and regioselectivity control. Herein, we report a palladium‐catalyzed, stereospecific, and ligand‐controlled regiodivergent glycosyl Suzuki–Miyaura coupling of 3‐boryl‐glycals, establishing a robust platform for glycoside diversification with versatile C1 and C3 modification. Notably, stable 3‐boryl‐glycals with 1,1,2,2‐tetraethylethylene glycol protection were first synthesized and fully characterized. Operating under mild conditions, this reaction enables the efficient synthesis of diverse 2,3‐unsaturated aryl/alkenyl C ‐glycosides with exceptional regio‐ and stereoselectivity. Importantly, this ligand‐controlled regiodivergent C ‐glycosylation offers a concise and efficient strategy for accessing 3‐ C ‐glycals (C3‐arylated/alkenylated glycals), circumventing time‐consuming and labor‐intensive multi‐step sequences. To elucidate the origins of regioselectivity control, we employ a data‐driven approach integrating DFT‐assisted multivariate regression analysis, identifying key ligand parameters that govern regioselectivity. Leveraging this predictive model, we pursued rational ligand design to enhance C3‐glycosylation selectivity and yield. Additionally, density functional theory calculations (DFT) provide critical insights into the fundamental principles dictating regioselectivity and tunability. These findings establish a solid foundation for advancing ligand‐controlled regiodivergent glycosylation reactions and significantly expand the synthetic toolkit for glycochemical synthesis.