Research Article

Nanomolar-scale high-throughput chemistry for the synthesis of complex molecules

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Science  20 Nov 2014:
DOI: 10.1126/science.1259203

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At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. In this space a miniaturized, high throughput experimentation (HTE) automation platform for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. However, carrying out automated, miniaturized chemistry is not easily compatible with the presence of solids or volatile organic solvents, so most of the synthetic “toolkit” cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, automation friendly reactions were developed to run in dimethylsulfoxide (DMSO) at room temperature. This advance enabled the robotics used in biotechnology to be coupled with emerging high throughput analysis (HTA) mass-spectrometric techniques to rapidly execute 1536 chemistry experiments in less than a day using as little as 0.02 mg of material per reaction.

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