Unlocking Chemical Space: Electrochemically Driven Synthesis of Glycosyl Bicyclo[1.1.1]pentane Frameworks

Image source: J. Am. Chem. Soc.Introduction: In the past decade, [1.1.1]propellane derivatives (BCPs) have provided a unique three-dimensional spatial structure for drug chemistry as superior bioelectronic scaffolds. Meanwhile, glycosyl derivatives play a crucial role in chemical biology and drug discovery due to their widespread presence in bioactive molecules. However, the potential of [1.1.1]propellane as a multifunctional scaffold in the field of glycoscience has not been fully explored. This article reports an electrochemical strategy for the synthesis of BCP-glycosides through the functionalization of [1.1.1]propellane by Professor Lutz Ackermann. By utilizing the electrochemical halogen atom transfer (e-XAT) process, a one-pot three-component reaction of glycosyl bromides, [1.1.1]propellane, and radical acceptors was achieved under mild conditions, resulting in the construction of glycosyl BCP-iodides, glycosyl BCP-H, and glycosyl BCP-boronate esters (Bpin) with excellent functional group tolerance and broad substrate applicability. Mechanistic studies indicate that the electrochemical process facilitates the generation of radical intermediates, which selectively add to [1.1.1]propellane and are subsequently captured by radical acceptors. This research establishes a multifunctional platform for the convenient synthesis of late-stage functionalization and superior scaffolds in drug discovery and chemical biology.Image source: J. Am. Chem. Soc.Image source: J. Am. Chem. Soc.

Conclusion:

An electrochemical strategy has been developed to construct diverse glycosyl BCP derivatives through the functionalization of [1.1.1]propellane. This method, initiated by the electrochemically driven XAT process, allows for the preparation of glycosyl BCP-iodides, BCP-hydrides, and BCP-boronate esters (Bpin) under mild conditions, demonstrating excellent functional group tolerance and broad substrate applicability. Mechanistic studies confirm the formation of α-glycosyl radical intermediates and propose a reasonable reaction pathway. This electrochemical platform enables efficient late-stage modifications of complex glycosyl substrates, including oligosaccharides, natural products, and drug-derived derivatives. Given the increasing application of BCPs as bioelectronic scaffolds in drug chemistry, this strategy provides a concise and general method for obtaining functionalized glycosyl BCP derivatives, with broad application prospects in drug discovery and chemical biology.

References:

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

J. Am. Chem. Soc. 2025

https://doi.org/10.1021/jacs.5c10732