Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1 electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron “late stage” approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched “chiral-at-BCP” bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.

The α‐aryl nitrile motif is a valuable pharmacophoric feature in medicinal chemistry. However, current synthetic methods to prepare this moiety frequently employ harsh reaction conditions, highly toxic cyanide reagents, or have a limited substrate scope. To address this, a mild photocatalytic cyanomethylation reaction was developed, employing an iridium/nickel metallaphotoredox system in conjunction with supersilanol, cyclopropyl bromide and a mild base, and blue light. To identify a robust set of conditions to efficiently couple acetonitrile to a range of aryl bromides, extensive High‐Throughput Experimentation (HTE) was first applied. Subsequently, Design‐of‐Experiments (DoE) scoping and then screening experiments were performed to identify significant factors and interactions. Due to evidence of non‐linear effects, this was followed by an optimization experiment using a central composite design. Finally, to confirm the conditions identified, a robustness DoE study was performed. The methodology demonstrated tolerance to a variety of functional groups, and was applicable to a range of medicinally‐relevant building blocks through library synthesis. The reaction was also applied to the multigram preparation of a key anti‐cancer Senexin intermediate, which shortened the synthetic route and obviated the need for a cyanide reagent.