Synthesis of Diverse Glycosyl Bicyclo[1.1.1]pentanes Enabled by Electrochemical Functionalization of [1.1.1]Propellane

Abstract

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 (e-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.