Despite the success of DNA encoded library (DEL) technology in new drug discovery and chemical biology, it’s great potential has not yet fully realized. One of the major obstacles is the synthesis of high-quality DELs with more chemical structural diversities, which in turn depend on the development of novel solution-phase DNA-compatible reactions. As the two general approaches in the DEL synthesis, conventional split-pool synthesis in the presence of DNA tag and late-stage DNA annotation of bioactive natural products (NPs) both require chemical reactions that are orthogonal to DNA tags in aqueous reaction condition. Thus, new methodologies that could access the greater structural diversities of DNA tagged small molecules attract attentions of the academia and pharmaceutical industry. Herein, we identified that (hetero) aryl fluorosulfonate (-OFS) is a versatile electrophile in palladium-catalyzed on-DNA Suzuki, Sonogashira, and Buchwald cross-coupling reactions. We have optimized reaction conditions in terms of function tolerability, DNA compatibility, and heterocyclic coupling partners’ diversity. Some of these reactions were facile at low temperature and under air. It is noteworthy, some of the catalytic systems distinguished between fluorosulfonate and other common electrophiles (Cl, Br), making them possible to carry out sequential on-DNA synthesis to form poly-substituted aryl and/or heteroaryl molecules in DELs. In addition, these new on-DNA coupling reactions could also be utilized in the late-stage on-NDA modifications of phenol containing natural products. Overall, these new DNA compatible reactions would provide more flexibilities in DEL’s design and synthesis in the future.

DNA-encoded libraries: Aryl fluorosulfonates as versatile electrophiles enabling facile on-DNA cross-coupling reactions

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.