A Radical Strategy to the Synthesis of Bicyclo[1.1.1]pentyl C−Glycosides

Abstract

Aryl C-glycosides, in which carbohydrates are directly linked to aryl fragments through a stable C–C bond, are an important class of biologically active molecules widely found in nature. These compounds exhibit resistance to (enzymatic) hydrolysis, a property that has been successfully leveraged in the development of metabolically stable drugs. On the other hand, despite their potential, three-dimensional analogues of aryl C-glycosides remain largely overlooked. Here, we present a three-component radical strategy that grants access to this underexplored chemical space. Here, glycosyl bromides serve as a source of glycosyl radicals, which can react with [1.1.1]propellane and a suitable SOMOphile to afford bicyclopentyl C-glycosides. These C(sp³)-rich analogues replace a planar aryl ring with a three-dimensional bicyclopentyl moiety, which is expected to enhance physicochemical properties. The protocol is practical, mild, and amenable to scalable synthesis in continuous flow. Experimental and computational studies support a radical chain mechanism under kinetic control.