Automation of Multistep Reaction-Based Solid-Phase Synthesis Using Novel Polystyrene-Coated Magnetic Particles

We have developed novel types of polystyrene-coated magnetic particles for versatile applications in multistep reaction-based solid-phase organic synthesis. These particles feature a protective polymer shell that allows them to function under various reaction conditions while maintaining the beneficial properties of traditional polystyrene beads, such as swelling and shrinking in organic solvents. We applied the particles in diverse multistep syntheses, including and combining amide couplings, nucleophilic aromatic substitutions, and Suzuki-Miyaura couplings at tens of micromole scale. The ferrimagnetic property of the particles enables their reversible immobilization using an external magnetic field, facilitating efficient reagent change cycles through simple aspiration of the separated supernatant liquid. This immobilization principle was applied to particle conditioning, reactions, washing, deprotection, and linker cleavage, allowing for fully automated parallel syntheses in microtiter plates using an automated liquid-handling system. This platform has already become routine for hit syntheses from various high-throughput screening campaigns and will enable the efficient production of a wide variety of new compounds by solid-phase synthesis. Ongoing developments on magnetic particles, reaction conditions, and automated processing will further extend the application range in medicinal chemistry and beyond.