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

Abstract

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.

Synthesis of (Trifluoromethyldiazirinyl)phenylboronic Acid Derivatives for Photoaffinity Labeling

“…6 Furthermore, it was reported that the reaction between diazirinyl halobenzenes and an arylboronic acid pinacol ester using a Pd catalyst afforded biaryl skeletons in lower yield. 7 Therefore, based on the stability of diazirine, we selected the synthetic pathway to construct the trifluoromethyldiazirinyl moiety in the phenylboronic acid derivatives. Preparations of trifluoroacetyl-substituted phenylboronic acid derivatives were essential for this synthetic pathway.…”

“…H-NMR (CDCl 3 ) δ: 7.97-7.93 (2H, m), 7.58-7.40 (2H, m), 1.37 (12H, s) 13. C-NMR (CDCl 3 ) δ: 147 7. and 147.6 (q, 2 J CF = 30.2 Hz), 136.8 and 136.5, 134.9 and 134.7, 131.1, 129.7 and 129.0, 127.9 and 127.8, 125.9 and 125.4, 120.7 and 118.4 (d, 1 J CF = 276.5 Hz), 84.4 and 84.3, 24.75.…”

Advancement in Organic Synthesis Through High Throughput Experimentation

“…In many instances HTE was used for identifying conditions appropriate for sensitive substrates or labile functional groups. Ichiishi et al [14] identified novel conditions that tolerated diazirine groups in the synthesis of photoaffinity probes. Cross-coupling reactions with diazirine containing substrates are extremely slow and have low yields because of their thermal instability and their propensity to act as competing coupling partners.…”

“…In many instances HTE was used for identifying conditions appropriate for sensitive substrates or labile functional groups. Ichiishi et al [14] . identified novel conditions that tolerated diazirine groups in the synthesis of photoaffinity probes.…”

Multigram Synthesis of Functionalized Spirocyclic Diazirines

“…The prominent role of spirocyclic diazirines in biomedical research,, , physical organic chemistry and organic synthesis, motivated us to challenge the synthesis of a series of diazirines derived from saturated carbo‐ and heterocycles with different ring size and substitution pattern. Since it was outlined that amide formation was the major reaction for diazirine photoaffinity labelling probes synthesis (43 % of the methods used), we have focused on the preparation of building blocks containing carboxylic acid and amine functions. In particular, we have aimed at a set of functionalized spirocyclic compounds containing diazirine fragment 6a–l (Figure ).…”