Multistep and multivectorial assembly line library synthesis in flow

Abstract

In drug discovery, traditional automated library synthesis has typically involved single-step synthetic procedures targeting a single vector of interest. However, achieving greater structural diversity requires exploring multistep and multivectorial approaches. These methodologies enable the preparation of compounds with varying structures in a single experiment. Here, we present a novel method for multistep library synthesis in continuous flow. This approach offers unique opportunities, such as exploring linkers between two defined vectors or rapidly mapping synergistic structure-activity relationships (SARs) by concurrently exploring multiple vectors. Our method incorporates up to eight different synthetic methodologies, including established chemistries, metal-catalyzed transformations, and modern metallaphotoredox couplings. This broad range of synthetic methodologies ensures a high level of diversity in the compounds generated, providing a powerful tool to accelerate the exploration of the chemical space in drug discovery programs.