High-throughput reaction screening using acoustic ejection mass spectrometry.

Area of Science:

• Chemical Synthesis
• Analytical Chemistry
• Mass Spectrometry

Background:

• High-throughput chemical synthesis is crucial for drug discovery and reaction optimization.
• Conventional analytical methods like liquid chromatography-mass spectrometry (LC-MS) create bottlenecks in high-throughput workflows.
• Need for faster, simpler quantitative detection methods in automated synthesis.

Purpose of the Study:

• To develop a streamlined quantitative detection method for high-throughput chemical synthesis.
• To enable rapid analysis of multiwell plates without sample-specific method customization.
• To demonstrate the application of acoustic ejection mass spectrometry (AEMS) for reaction monitoring.

Main Methods:

• Utilized tandem mass spectrometry with acoustic ejection mass spectrometry (AEMS) for direct sample analysis.
• Developed a method based on a characteristic neutral loss fragment common to starting materials and products.
• Analyzed 384-well plates of chemical reaction data.

Main Results:

• Achieved accurate quantification with simple method development for reactions sharing a specific fragmentation signature.
• Collected data from 384-well plates at a pace comparable to two LC-MS samples with similar accuracy.
• Successfully applied the method to four common medicinal chemistry transformations (C-N and C-C bond formation).
• Demonstrated utility in synthesizing analogs of molecular glues, antifungals, antibiotics, and building blocks for automated synthesis.

Conclusions:

• Acoustic ejection mass spectrometry offers a rapid and accurate solution for quantitative detection in high-throughput chemical synthesis.
• The developed method significantly reduces analytical bottlenecks, accelerating compound library generation and reaction optimization.
• This approach is versatile and applicable to various medicinal chemistry transformations, supporting automated small molecule synthesis.