Thinking Outside the Library: Cluster Synthesis of Diverse Molecules on a Single Robotic Platform

Abstract

The development of a general autonomous platform for organic synthesis that enables faster, flexible and efficient delivery of target molecules is an attractive strategy for many fields such as drug discovery and material sciences. Traditionally, automated parallel synthesis relies on the synthesis of libraries of various sizes, sharing the same transformations and name reactions with defined reaction conditions. Herein, we report on the development of our platform and a paradigm shift in high-throughput robotic synthesis: from mono-reaction type libraries to multi-reaction type clusters. This fundamentally distinct approach differs from the current strategies by clustering reactions based on their reaction conditions, defined as ranges of acceptable temperature and time by expert chemists.As a result, many different reactivities can be merged in a cluster. An algorithm has been developed to help chemists organize the workload in the minimum number of clusters taking into account the physical and chemical constraints of the platform. We applied this strategy to organize efficiently the synthesis of 135 molecules, using 27 different name reactions in only 6 clusters and 3 synthetic campaigns.