Acoustic Droplet Ejection Enabled Automated Reaction Scouting.

Area of Science:

• Organic Chemistry
• Chemical Engineering
• Drug Discovery

Background:

• Accelerating synthetic chemistry is crucial for optimizing properties in pharmaceutical, agrochemical, and materials research.
• Traditional organic synthesis methods are often slow, sequential, and material-intensive, limiting throughput for multiple substrate combinations.

Purpose of the Study:

• To introduce acoustic droplet ejection (ADE) technology for miniaturized and accelerated small-molecule synthesis.
• To demonstrate the application of ADE in scouting a novel isoquinoline synthesis and scaling up reactions.

Main Methods:

• Utilized acoustic droplet ejection (ADE) for precise, touchless transfer of nanoliter (nL) droplets of building blocks.
• Automated synthesis of 384 random isoquinoline derivatives in discrete wells.
• Quality control of synthesized compounds using SFC-MS and TLC-UV-MS analysis.

Main Results:

• Successfully synthesized 384 random isoquinoline derivatives using automated ADE technology.
• Demonstrated a pipeline from nmol-scale scouting to mmol- and mol-scale synthesis.
• Identified a novel reaction with broad scope through efficient screening.

Conclusions:

• Acoustic droplet ejection (ADE) technology significantly enhances the speed and efficiency of small-molecule synthesis.
• ADE facilitates rapid property optimization and reaction discovery through automated, miniaturized screening.
• This approach enables a seamless transition from initial discovery to larger-scale synthesis.