Thianthrenium-enabled modular synthesis of bicyclo[1.1.1]pentanes

Abstract The incorporation of three-dimensional small-ring scaffolds into bioactive molecules can enhance metabolic stability and solubility. Over the last decade, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres for para -substituted benzene rings in drug discovery. However, BCP synthesis typically requires de novo synthesis from volatile [1.1.1]propellane, whereas more stable BCP reagents, such as alkyl BCP iodides, allow modification at only one end, limiting their application to end groups. Here we describe a stable, bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT + ) reagent for modular BCP bioisostere production. The cationic thianthrenium group at the neopentyl site of IBM-TT + facilitates chemoselective substitutions through electrostatic interactions, overcoming the high energy barriers of bimolecular nucleophilic substitution (S N 2) at neopentyl sites. The retained BCP iodide functionality serves as a second versatile handle for metal–halogen exchange, photoredox chemistry or transition-metal catalysis. The dual reactivity of IBM-TT + allows synthesis of a multitude of BCP bioisosteres for benzyl amines, ethers, esters, thioethers and diarylmethanes.