Development of on-DNA Formation of Benzofuran for DNA-Encoded Library Synthesis
Organic Letters Publication Summary:
For over three decades, DNA-encoded library technology has experienced significant growth, emerging as a robust methodology for hit discovery services. It grants access to vast collections of small molecules on DNA, facilitating hit identification. Despite the capability of on-DNA combinatorial synthesis to generate billion-sized libraries simultaneously, the diversity of DNA-encoded compounds has been limited by the range of chemical transformations available. Encouraged by recent studies we published demonstrating the integration of alkyne-based units into DNA-encoded libraries (DELs), our focus shifted towards exploring a previously unexplored category of on-DNA heterocycles: benzofurans. These heterocycles exhibit a broad spectrum of pharmacological properties, including anti-inflammatory, antimicrobial, antiviral, anticancer, and central nervous system (CNS) activities. They have been investigated as potential drug candidates for the treatment of various diseases, including cancer, cardiovascular disorders, neurodegenerative diseases, and infectious diseases.
Through the application of a novel homologation-heterocyclization synthetic cascade, we have developed a method for on-DNA synthesis of benzofurans from aldehydes. This methodology involves an inventive application of the Seyferth-Gilbert homologation, followed by a highly efficient Sonogashira coupling and intramolecular cyclization in a one-pot, two-step fashion. The resulting approach presents a robust and distinctive route for synthesizing a diverse array of pharmaceutically relevant benzofuran-based scaffolds within DNA-encoded libraries (DELs).
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