biostudies-literatureLiu JEuropean Research Council34813-34822https://www.ebi.ac.uk/biostudies/studies/S-EPMC12465002biostudies-literatureUnknown147(38)Over the past decade, bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres of aromatic rings, offering unique three-dimensional architectures for medicinal chemistry. Meanwhile, glycosyl derivatives play a pivotal role in chemical biology and drug discovery due to their widespread presence in biologically active molecules; however, the potential of bicyclo[1.1.1]pentanes (BCPs) as versatile scaffolds in glycoscience remains largely unexplored. Herein, we report an electrochemistry strategy for the synthesis of BCP-glycosides via the functionalization of [1.1.1]propellane. By leveraging an electrochemical halogen-atom transfer (<i>e</i>-XAT) process, we achieved a one-step, three-component reaction of glycosyl bromides, [1.1.1]propellane, and radical acceptors under mild conditions, enabling the construction of glycosyl BCP-iodides, glycosyl BCP-H, and glycosyl BCP-pinacolboronic esters (Bpins) with exceptional functional group tolerance and scalability. Mechanistic studies suggested that the electrochemical process facilitated the generation of radical intermediates, which underwent selective addition to [1.1.1]propellane, followed by trapping with radical acceptors. This study establishes a versatile platform for late-stage functionalization and streamlined access to privileged scaffolds in drug discovery and chemical biology.Journal of the American Chemical SocietySynthesis of Diverse Glycosyl Bicyclo[1.1.1]pentanes Enabled by Electrochemical Functionalization of [1.1.1]Propellane.PMC12465002101021358Warratz SHinrichs FLiu JSurke MPurushothaman RAckermann LfalseSynthesis of Diverse Glycosyl Bicyclo[1.1.1]pentanes Enabled by Electrochemical Functionalization of [1.1.1]Propellane.Over the past decade, bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres of aromatic rings, offering unique three-dimensional architectures for medicinal chemistry. Meanwhile, glycosyl derivatives play a pivotal role in chemical biology and drug discovery due to their widespread presence in biologically active molecules; however, the potential of bicyclo[1.1.1]pentanes (BCPs) as versatile scaffolds in glycoscience remains largely unexplored. Herein, we report an electrochemistry strategy for the synthesis of BCP-glycosides via the functionalization of [1.1.1]propellane. By leveraging an electrochemical halogen-atom transfer (<i>e</i>-XAT) process, we achieved a one-step, three-component reaction of glycosyl bromides, [1.1.1]propellane, and radical acceptors under mild conditions, enabling the construction of glycosyl BCP-iodides, glycosyl BCP-H, and glycosyl BCP-pinacolboronic esters (Bpins) with exceptional functional group tolerance and scalability. Mechanistic studies suggested that the electrochemical process facilitated the generation of radical intermediates, which underwent selective addition to [1.1.1]propellane, followed by trapping with radical acceptors. This study establishes a versatile platform for late-stage functionalization and streamlined access to privileged scaffolds in drug discovery and chemical biology.2025-01-01T00:00:00Z2025 Sep2026-06-03T21:16:47.413Z2026-05-01T03:10:54.443ZS-EPMC124650024094820410.1021/jacs.5c10732