Miniaturization of popular reactions from the medicinal chemists' toolbox for ultrahigh-throughput experimentation

Miniaturization is a tactic employed in many technologies to accelerate discovery through parallelized data collection. The miniaturization of chemical synthesis to the limits of chemoanalytical and bioanalytical detection could accelerate drug discovery by increasing the amount of experimental data collected per milligram of material consumed. Here we demonstrate the miniaturization of popular reactions used in drug discovery such as reductive amination, N-alkylation, N-Boc (tert-butyloxycarbonyl) deprotection and Suzuki coupling for utilization in 1.2 mu l reaction droplets. Reaction methods were evolved to perform in high-boiling solvents at room temperature, enabling the diversification of precious starting materials, such as the complex natural product staurosporine.The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, ultraHTE-amenable reaction conditions are developed through miniaturization of four of the most important drug discovery transformations, and their generality and scalability are tested on a range of natural products and drug candidates.