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The synthesis of DNA-encoded libraries (DELs) is a critical drug discovery technology that enables the rapid generation of billions of DNA-tagged compounds. However, a barrier to on-DNA reaction development in academic laboratories is the need for dedicated instrumentation for ion-pairing reversed-phased liquid chromatography-mass spectrometry (IP-RP LC-MS), which is required for reaction monitoring and analysis. In this work, we report the use of a hydrophilic interaction chromatography (HILIC) LC-MS method with an MS-friendly mobile phase as a convenient way to desalt and resolve crude mixtures. This approach allows academic labs to easily translate reaction and sample preparation protocols directly from the literature. HILIC-LC-MS analysis was employed in diverse oxidative three-component click reactions on-DNA that display broad substrate tolerance and observable damage to the DNA. This work not only provides access to new heterocyclic compounds libraries, but offers new tools and inspiration for continued on-DNA reaction development by academic labs due to its ease of setup and analysis.
Hu et al. (Thu,) studied this question.