A Cross-Coupling Approach to Synthesis Of BEPs: Faster Access to Probe Conditions

The Michel Group has recently reported fluorescent small molecule probes for the detection of ethylene, a hormone released during key life cycle events in plants and commonly associated with fruit ripening. To improve the sensitivity and selectivity of these probes, it is necessary to synthesize analogues and evaluate how structural changes will influence photophysical properties such as limit of detection and fluorescence turn-on. However, the previous approach to this synthesis relied on a laborious multi-step process that requires significant time and resource commitments for each new probe. To overcome this synthetic challenge, we developed a convergent synthetic approach that reacts two advanced intermediates using a Palladium (Pd)-catalyzed cross coupling. Initially, a series of coupling partners, catalysts, and reaction conditions were evaluated to optimize the cross-coupling reaction. Once conditions were favorable, a series of different substituents on the aromatic rings of the probe were tested for their influence on photophysical properties. Results indicate that structural modifications can improve the brightness of the BODIPY fluorophore, but more data is needed on how they can be used to strengthen other properties such as lowering background fluorescence turn-on and limit of detection. Overall, a convergent synthetic approach increases the accessibility of BODIPY Ethylene Probe (BEP) analogues, allowing for more rapid evaluation of these structural modifications. Additionally, the reported cross-coupling conditions are valuable to other researchers working in fluorescent probe synthesis.