Readily Accessible High-Throughput Experimentation: A General Protocol for the Preparation of ChemBeads and EnzyBeads

Abstract

Chemical-and enzyme-coated beads (ChemBeads and EnzyBeads) were introduced recently as a universal strategy for the accurate dispensing of various solids in submilligram quantities using automated instrumentation or manual dispensing. The coated beads are prepared using a resonant acoustic mixer (RAM)�an instrument that may be available only to wellestablished facilities. In this study, we evaluated alternative coating methods for preparing ChemBeads and EnzyBeads without the use of a RAM. We also evaluated the effects of bead sizes on loading accuracy using 4 coating methods and 12 solids (9 chemicals and 3 enzymes) as test subjects. While our original RAM coating method is the most versatile for the broadest range of solids, high-quality ChemBeads and EnzyBeads that are suitable for high-throughput experimentation can be prepared using alternative methods. These results should make ChemBeads and EnzyBeads readily accessible as the core technology for setting up high-throughput experimentation platforms.

Utilization of High-Throughput Experimentation (HTE) and ChemBeads Toward the Development of an Aryl Bromide and Benzyl Bromide Photoredox Cross-Electrophile Coupling

“…To address these operational difficulties, we were excited by reports on the use of ChemBeads for the accurate measurement of reagents on small scale (10 μmol) and for dosing reagents that are poorly soluble in organic solvents. 11 Consequently, we decided to evaluate ChemBeads on the photoredox screening platform. Concurrently with our efforts, it was recently reported that there are no negative effects of adding beads to the reaction wells, including not impacting light penetration or disrupting efficient mixing.…”

“…During the course of our screening plate development, we observed the poor solubility of the sodium carbonate base and Ni­(dtbbpy)­Cl 2 precatalyst in the organic solvents chosen and the hard-to-dose sticky nature of Si-1 complicated the screening process and raised potential reproducibility issues. To address these operational difficulties, we were excited by reports on the use of ChemBeads for the accurate measurement of reagents on small scale (10 μmol) and for dosing reagents that are poorly soluble in organic solvents . Consequently, we decided to evaluate ChemBeads on the photoredox screening platform.…”

At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research

“…37 ChemBeads can be prepared via resonant acoustic mixing, vortexing, or shaking by hand to coat solid reagents onto small chemically inert glass beads. 41 This process unifies the properties of the solids to those of the glass beads and increases requisite reagent mass, enabling faster and simpler dispensing, either manually or using automation. This technology was applied to the optimization of photoredox cross-couplings with the development of photocatalyst-and nickel catalyst-coated ChemBeads, resulting in expedited photoredox HTE reaction setup (Figure 4A).…”

“…To expand HTE accessibility internally and streamline experiment setup, our group developed chemical-coated glass beads, or ChemBeads, as a technology that enables the reliable dispensing of solid reagents at the submilligram scale (Figure A) . ChemBeads can be prepared via resonant acoustic mixing, vortexing, or shaking by hand to coat solid reagents onto small chemically inert glass beads . This process unifies the properties of the solids to those of the glass beads and increases requisite reagent mass, enabling faster and simpler dispensing, either manually or using automation.…”

A Platform for the Liebeskind–Srogl Coupling of Heteroaromatic Thioethers for Medicinal-Chemistry-Relevant Transformations

“…In parallel to identifying the scope of our LSC platform, we worked on rendering it amenable to high-throughput experimentation (HTE): We enabled 96-well screening at the micromolar scale using ChemBead technology. − Using two example transformations, we juxtaposed the outcomes of a Pd-ligand screen to explore trends in stereoelectronic properties of Pd-catalysts using a standard Buchwald-ligand kit, with the ones for two commercially available copper species (Figure A). To our surprise, we did not observe any significant difference between the Pd species, where we would normally expect the effects of electron-releasing abilities and steric bulk to display a certain trend.…”