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.