DNA-encoded chemical libraries (DECLs) are pools of small molecule–DNA conjugates in which the covalently attached DNA serves as an encoding tag for each connected small molecule structure. By utilizing next-generation DNA sequencing technologies, DECLs may be used to discover small-molecule binders to biological targets through affinity-based “selection” experiments. Although DECLs sample a large amount of chemical space, the available repertoire of chemical transformations to construct these libraries is limited. Herein we report our studies on the adaption of two useful chemical transformations, ring-closing olefin metathesis (RCM) and palladium-catalyzed hydroxycarbonylation, to DNA–chemical conjugates and their application towards DECL synthesis. Ring-closing metathesis is a powerful transformation to create macrocycles, and although regularly used in drug synthesis, has found limited application in biological substrates due to the challenges posed by unmasked Lewis-basic sites. Our studies build upon previous work on DNA-compatible RCM by greatly expanding the substrate scope, functional group compatibility and product conversions through use of an unusual RCM catalyst and novel DNA-shielding system. Post-RCM DNA sequencing studies and applications to complex on-DNA substrates are also reported. Palladium-catalyzed hydroxycarbonylation is a process in which carbon monoxide migrates into a palladium-inserted electrophile with subsequent hydroxide capture to ultimately form a carboxylic acid. As most reported DECLs involve at least one cycle of amidation, this transformation could find routine use in DECL synthesis. Herein, we report our findings on the development of a DNA-compatible hydroxycarbonylation using in situ generated carbon monoxide. With our optimized conditions, a broad range of aryl and heteroaryl iodides and bromides could be converted to the corresponding carboxylic acids and, after demonstration of DNA-compatibility, this transformation was applied in the synthesis of a DECL of ~81 million compounds.

Adaption of ring-closing olefin metathesis and palladium-catalyzed hydroxycarbonylation reactions to a DNA-encoded chemical library platform

2019 Fall National Meeting

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