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

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.