Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki–Miyaura Cross Coupling Reaction

Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki–Miyaura (S–M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S–M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model S–M coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment. This screen identified reaction conditions that gave good yields of S–M coupling product while minimally perturbing the diazirine reporter fragment. These conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of 24 pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic efficiency